Spirocyclic compounds

ABSTRACT

The present invention provides compounds which bind to the ubiquitously expressed E3 ligase protein cereblon (CRBN) and their use for the treatment of abnormal cellular proliferation. The present invention also provides compounds that may be used as synthetic intermediates in the synthesis of bifunctional compounds used for targeted protein degradation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US2019/027747, filed in the International Patent Cooperation Treaty,U.S. Receiving Office on Apr. 16, 2019, which claims the benefit ofEuropean Patent Application No. EP18167561, filed Apr. 16, 2018, andEuropean Patent Application No. EP18168269, filed Apr. 19, 2018. Theentirety of these applications is hereby incorporated by referenceherein for all purposes.

FIELD OF THE INVENTION

The present invention provides compounds which bind to the ubiquitouslyexpressed E3 ligase protein cereblon (CRBN), which can alter thesubstrate specificity of the CRBN E3 ubiquitin ligase complex, resultingin breakdown of intrinsic downstream proteins. The present inventionalso provides compounds that can be used as synthetic intermediates inthe preparation of bifunctional compounds for use in targeted proteindegradation. The present compounds are thus useful for the treatment orprophylaxis of abnormal cellular proliferation, including tumors andcancer.

BACKGROUND OF THE INVENTION

Protein degradation is a highly regulated and essential process thatmaintains cellular homeostasis. The selective identification and removalof damaged, misfolded, or excess proteins is achieved via theubiquitin-proteasome pathway (UPP). The UPP is central to the regulationof almost all cellular processes, including antigen processing,apoptosis, biogenesis of organelles, cell cycling, DNA transcription andrepair, differentiation and development, immune response andinflammation, neural and muscular degeneration, morphogenesis of neuralnetworks, modulation of cell surface receptors, ion channels and thesecretory pathway, the response to stress and extracellular modulators,ribosome biogenesis and viral infection.

Covalent attachment of multiple ubiquitin molecules by an E3 ubiquitinligase to a terminal lysine residue marks the protein for proteasomedegradation, where the protein is digested into small peptides andeventually into its constituent amino acids that serve as buildingblocks for new proteins. Defective proteasomal degradation has beenlinked to a variety of clinical disorders including Alzheimer's disease,Parkinson's disease, Huntington's disease, muscular dystrophies,cardiovascular disease, and cancer among others.

There are over 600 E3 ubiquitin ligases which facilitate theubiquitination of different proteins in vivo, which can be divided intofour families: HECT-domain E3s, U-box E3s, monomeric RING E3s andmulti-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487)titled “Genome-wide and functional annotation of human E3 ubiquitinligases identifies MULAN, a mitochondrial E3 that regulates theorganelle's dynamics and signaling.”; Berndsen et al. (Nat. Struct. Mol.Biol., 2014, 21, 301-307) titled “New insights into ubiquitin E3 ligasemechanism”; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434)titled “RING domain E3 ubiquitin ligases.”; Spratt et al. (Biochem.2014, 458, 421-437) titled “RBR E3 ubiquitin ligases: new structures,new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014,14, 233-347) titled “Roles of F-box proteins in cancer.”

Cereblon is a protein that in humans is encoded by the CRBN gene. CRBNorthologs are highly conserved from plants to humans, which underscoresits physiological importance. Cereblon forms part of an E3 ubiquitinligase protein complex which interacts with damaged DNA binding protein1 (DDB1), forming an E3 ubiquitin ligase complex with Cullin 4 (CUL4A)and the E2-binding protein ROC1 (also known as RBX1) where it functionsas a substrate receptor to select proteins for ubiquitination. Through amechanism that has not been completely elucidated, cereblonubiquitination of target proteins results in increased levels offibroblast growth factor 8 (FGF8) and fibroblast growth factor 10(FGF10). FGF8 in turn regulates a number of developmental processes,such as limb and auditory vesicle formation. The net result is that thisE3 ubiquitin ligase complex is important for limb outgrowth in embryos.In the absence of cereblon, DDB1 forms a complex with DDB2 thatfunctions as a DNA damage-binding protein.

In unrelated parallel research, Ito et al. (Science 2010, 327,1345-1350) titled “Identification of a Primary Target of ThalidomideTeratogenicity”, described that cereblon is a thalidomide bindingprotein. The study revealed that thalidomide-cereblon binding in vivomay be responsible for thalidomide teratogenicity. After the discoverythat thalidomide causes teratogenicity in the mid-1960′s, the compoundand related structures were notwithstanding found to be useful asanti-inflammatory, anti-angiogenic and anti-cancer agents (see Bartlettet al. (Nat. Rev. Cancer 2004, 4, 314-322) titled “The Evolution ofThalidomide and Its Imid Derivatives as Anticancer Agents”). Thalidomidehas been approved for the treatment of certain neoplastic diseases,including multiple myeloma, and is currently under investigation for usein treating a variety of other types of cancer along with the structuralderivatives lenalidomide and pomalidomide (see Martiniani, R. et al.“Biological activity of lenalidomide and its underlying therapeuticeffects in multiple myeloma” Adv Hematol, 2012, 2012:842945; and Terpos,E. et al. “Pomalidomide: a novel drug to treat relapsed and refractorymultiple myeloma” Oncotargets and Therapy, 2013, 6:531).

The disclosure that thalidomide binds to the cereblon E3 ubiquitinligase led to research to investigate incorporating thalidomide andcertain derivatives into compounds for the targeted destruction ofproteins. Celgene has disclosed imids for similar uses, including thosein U.S. Pat. Nos. 6,045,501; 6,315,720; 6,395,754; 6,561,976; 6,561,977;6,755,784; 6,869,399; 6,908,432; 7,141,018; 7,230,012; 7,820,697;7,874,984; 7,959,566; 8,204,763; 8,315,886; 8,589,188; 8,626,531;8,673,939; 8,735,428; 8,741,929; 8,828,427; 9,056,120; 9,101,621; and9,101,622.

Patent applications filed by C4 Therapeutics, Inc., that describecompounds capable of binding to an E3 ubiquitin ligase and a targetprotein for degradation include: WO 2017/197051 titled “Amine-LinkedC3-Glutarimide Degronimers for Target Protein Degradation”; WO2017/197055 titled “Heterocyclic Degronimers for Target ProteinDegradation”; WO 2017/197036 titled “Spirocyclic Degronimers for TargetProtein Degradation”; WO 2017/197046 20 titled “C3-Carbon LinkedGlutarimide Degronimers for Target Protein Degradation”; WO 2017/197056titled “Bromodomain Targeting Degronimers for Target ProteinDegradation.”; and WO 2018/237026 titled “N/O-Linked Degrons andDegronimers for Protein Degradation.”

Other patent applications that describe protein degrading compoundsinclude: WO 2015/160845; WO 2016/105518; WO 2016/118666; WO 2016/149668;WO 2016/197032; WO 2016/197114; WO 2017/007612; WO 2017/011371; WO2017/011590; WO 2017/030814; WO 25 2017/046036; WO 2017/176708; WO2017/176957; WO 2017/180417; WO 2018/052945; WO 2018/052949; WO2018/053354; WO 2018/071606; WO 2018/102067; WO 2018/102725; WO2018/118598; WO 2018/119357; WO 2018/119441; WO 2018/119448; WO2018/140809; WO 2018/144649; and WO 2018/226542. Other relevant patentapplications include: WO 2013/020557; WO 2013/063560; WO 2013/106643; WO2016/011906; WO 2017/024318; and WO 2017/117473.

Additional compound publications include: US 2012/071459; WO2003/020721; WO 2011/025690; WO 2012/176123; WO 2013/020557; WO2013/063560; WO 2013/106643; WO 2013/124026; WO 2015/031036; WO2015/160845; WO 2016/011906; WO 2016/022644; WO 2016/105518; WO2017/007612; WO 2017/024318; WO 2017/117473; WO 2017/189386; WO2018/005591; U.S. Pat. No. 9,206,142;

There is a need for new compounds and methods of treatment that bind tothe E3 ligase protein cereblon for use in the treatment of variousmedical conditions, notably abnormal cellular proliferation. There isalso a need for new compounds that may be used in the preparation ofbifunctional molecules that are used in the degradation of proteins thatare involved in disease processes.

SUMMARY OF THE INVENTION

In a first aspect, compounds and their uses and manufacture are providedthat bind to cereblon and enhance the ubiquitination of proteins by acereblon-containing E3 ubiquitin ligase complex, which results inprotein degradation and thus is useful for the treatment of abnormalcellular proliferation and other disorders as described herein. In asecond aspect, compounds are provided that contain a chemical moietycapable of binding to cereblon, which can be used as syntheticintermediates in the preparation of bifunctional compounds that causedegradation of a selected protein via the ubiquitin proteasome pathway(UPP).

The compounds described herein can be administered to a host, forexample, a human, in need thereof, in an effective amount, optionally asa pharmaceutically acceptable salt, and optionally in a pharmaceuticallyacceptable composition. The compounds can be administered for anytherapeutic indication which can be treated by modulating the functionor activity of the cereblon-containing E3 Ubiquitin Ligase ProteinComplex, including but not limited to the treatment of abnormal cellproliferation, such as cancer or a tumor. In certain embodiments, thecompounds as described herein can modulate the natural activity ofcereblon.

The invention includes new compounds of Formula Ia, Formula Ib, FormulaII, Formula III a, Formula IIIb, Formula IV, Formula V, Formula VI,Formula VIII, Formula IX, Formula X, Formula XI, and Formula XII. Inaddition, the invention includes the use of compounds generally inFormula VII and Formula XIII for the treatment of a therapeuticcondition that can be treated by modulating the function or activity ofthe cereblon-containing E3 Ubiquitin Ligase Protein Complex. Theinvention also includes the use of compounds generally in Formula XIVand Formula XV in the preparation of bifunctional compounds that degradea target protein by the ubiquitin proteasome pathway (UPP). Theinvention also includes compounds of Formula XIV-a, Formula XIV-b,Formula XIV-c, Formula XIV-d, Formula XIV-e, Formula XIV-f, FormulaXIV-g, Formula XIV-h, Formula XIV-i, Formula XIV-j, Formula XIV-k,Formula XIV-1, Formula XIV-m, Formula XIV-n, Formula XIV-o, FormulaXIV-p, Formula XIV-q, Formula XIV-r, Formula XIV-s, Formula XIV-t,Formula XIV-u, Formula XIV-v, Formula XIV-w, Formula XIV-x, FormulaXV-a, Formula XV-b, Formula XV-c, Formula XV-d, Formula XV-e, FormulaXV-f, Formula XV-g, Formula XV-h, Formula XV-i, Formula XV-j, FormulaXV-k, Formula XV-m, Formula XV-n, Formula XV-o, Formula XV-p, FormulaXV-q, Formula XV-r, Formula XV-s, and Formula XV-t.

In one aspect, a compound is provided of Formula Ia or Formula Ib:

or a pharmaceutically acceptable salt thereof;

wherein:

X^(1a) is selected from aryl and aryl substituted by R^(2a);

X^(1b) is selected from aryl and aryl substituted by R^(2b);

R¹ is absent or ═O;

R^(2a) is selected from the group consisting of: —C(═O)—O—C₁₋₆-alkyl;—NH—C(═O)—C₁₋₆-alkyl; —NH₂; —OH; and —NO₂; and

R^(2b) is selected from the group consisting of: —C(═O)—O—C₁₋₆-alkyl;—NH—C(═O)—C₁₋₆-alkyl; —NH₂; and —NO₂.

In another aspect, a compound is provided of Formula II:

or a pharmaceutically acceptable salt thereof;

wherein:

X^(2a) is selected from the group consisting of heterocyclyl,heterocyclyl substituted by R³, heteroaryl, heteroaryl substituted byR⁴, and C₁₋₆-alkyl;

R³ is selected from the group consisting of —C(═O)—C₁₋₆-alkyl and =0;

R⁴ is selected from the group consisting of —C(═O)—O—C₁₋₆-alkyl;C₁₋₆alkyl; —NH₂; —NH—C(═O)—C₁₋₆-alkyl; and —NO₂;

and all other variables are as defined herein.

In another aspect, a compound is provided of Formula IIIa or FormulaIIIb:

or a pharmaceutically acceptable salt thereof;

wherein:

X¹ is selected from the group consisting of aryl and aryl substitutedwith R^(2c);

X^(1d) is selected from the group consisting of aryl and arylsubstituted with R^(2d);

R^(2c) is selected from the group consisting of: —C(═O)—O—C₁₋₆-alkyl;—NH—C(═O)—C₁₋₆-alkyl; and —NO₂;

R^(2d) is selected from the group consisting of: —C(═O)—O—C₁₋₆-alkyl;—NH—C(═O)—C₁₋₆-alkyl; —NH₂; and —NO₂;

and all other variables are as defined herein.

In another embodiment, a compound of Formula IV is provided:

or a pharmaceutically acceptable salt thereof;

wherein:

X^(3a) is selected from the group consisting of hydrogen, heterocyclyl,heterocyclyl substituted by R³, heteroaryl, heteroaryl substituted byR⁴, and C₁₋₆-alkyl;

and all other variables are as defined herein.

In another embodiment, a compound of Formula V or VI is provided:

or a pharmaceutically acceptable salt thereof;

wherein:

X^(4a) is selected from the group consisting of hydrogen, aryl, arylsubstituted by R², heterocyclyl, heterocyclyl substituted by R³,heteroaryl, heteroaryl substituted by R⁴, and C₁₋₆-alkyl;

R² is selected from the group consisting of: —C(═O)—O—C₁₋₆-alkyl;—NH—C(═O)—C₁₋₆-alkyl; —NH₂; —OH; and —NO₂;

R⁵ is C₁₋₆-alkyl;

and all other variables are as defined herein.

In another aspect, the use of a compound for the treatment of atherapeutic condition which can be treated by modulating the function oractivity of the cereblon containing E3 Ubiquitin Ligase Protein Complexis provided of Formula VII:

or a pharmaceutically acceptable salt thereof;

wherein:

Y^(A) is absent or selected from the group consisting of: —C(═O)—;—C(═O)—C(H,C₁₋₆-alkyl)-; and —C(═O)—CH₂—;

X^(A) is selected from the group consisting of: hydrogen; aryl; arylsubstituted by R²; heterocyclyl; heterocyclyl substituted by R³;heteroaryl; heteroaryl substituted by R⁴; and C₁₋₆-alkyl;

wherein if Y^(A) is absent, then X^(A) cannot be hydrogen;

and all other variables are as defined herein.

In another aspect, a compound is provided of Formula VIII:

or a pharmaceutically acceptable salt thereof;

wherein:

A is selected from the group consisting of CH₂ and NH;

X^(5a) is aryl substituted by R^(6a); and

R^(6a) is selected from the group consisting of: —C(═O)—OH;—NH—C(═O)—C₁₋₆-alkyl; and —NO₂.

In another aspect, a compound is provided of Formula IX:

or a pharmaceutically acceptable salt thereof;

wherein X⁶′ is aryl substituted with —C(═O)—OH.

In another aspect, a compound is provided of Formula X:

or a pharmaceutically acceptable salt thereof;

wherein:

X^(B) is selected from the group consisting of: aryl; aryl substitutedby R⁶; heteroaryl; and heteroaryl substituted by R⁷;

R⁶ is selected from the group consisting of: —C(═O)—OH;—NH—C(═O)—C₁₋₆-alkyl; —NH₂; and —NO2; and

R⁷ is selected from the group consisting of: —C(═O)—OH;—C(═O)—O—C₁₋₆-alkyl; —NH₂; and —NO₂.

In another aspect, a compound is provided of Formula XI:

or a pharmaceutically acceptable salt thereof;

wherein X^(7a) is selected from the group consisting of heteroaryl andheteroaryl substituted by R⁷.

In another aspect, a compound is provided of Formula XII:

or a pharmaceutically acceptable salt thereof;

wherein:

Y^(B) is absent or —C(═O)—;

X^(8a) heteroaryl substituted by R^(7a); and

R^(7a) is selected from the group consisting of —C(═O)—OH and—C(═O)—O—C₁₋₆-alkyl.

In another aspect, the use of a compound for the treatment of atherapeutic condition which can be treated by modulating the function oractivity of the cereblon containing E3 Ubiquitin Ligase Protein Complexis provided of Formula XIII:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

The compounds of Formula Ia, Formula Ib, Formula II, Formula IIIa,Formula IIIb, Formula IV, Formula V, Formula VI, Formula VIII, FormulaIX, Formula X, Formula XI, and Formula XII are useful as therapeuticagents when administered in an effective amount to a host, typically ahuman, for the treatment of a medical disorder including, but notlimited to, abnormal cellular proliferation, including a tumor orcancer, or a myelo- or lymphoproliferative disorder such as B- or T-celllymphomas, multiple myeloma, Waldenstrom's macroglobulinemia,Wiskott-Aldrich syndrome, or a post-transplant lymphoproliferativedisorder; an immune disorder, including autoimmune disorder such asAddison disease, Celiac disease, Dermatomyositis, Graves disease,thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis,lupus, or type I diabetes; a disease of cardiologic malfunctionincluding hypercholesterolemia; an infectious disease including viral orbacterial infections; inflammatory conditions including asthma, chronicpeptic ulcers, tuberculosis, rheumatoid arthritis, periodontitis,ulcerative colitis, Crohn's disease, or hepatitis.

In certain embodiments, the present invention provides theadministration of an effective amount of a compound of Formula Ia,Formula Ib, Formula II, Formula IIIa, Formula IIIb, Formula IV, FormulaV, Formula VI, Formula VIII, Formula IX, Formula X, Formula XI, andFormula XII to treat a patient, for example a human, having aninfectious disease, wherein the therapy acts via binding to cereblon orits E3 Ubiquitin Ligase or acts through an independent mechanism,optionally in combination with another bioactive agent. The diseasestate or condition may be caused by a microbial agent or other exogenousagent such as a virus (as non-limiting examples, HIV, HBV, HCV, HSV,HPV, RSV, CMV, Ebola, Flavivirus, Pestivirus, Rotavirus, Influenza,Coronavirus, EBV, viral pneumonia, drug-resistant viruses, Bird Flu, RNAvirus, DNA virus, adenovirus, poxvirus, Picornavirus, Togavirus,Orthomyxovirus, Retrovirus, or Hepadovirus), bacterial (including butnot limited to Gram-negative, Gram-positive, Atypical, Staphylococcus,Streptococcus, E. Coli, Salmonella, Helicobacter pylori, meningitis,gonorrhea, Chlamydiaceae, Mycoplasmataceae, etc.), fungus, protozoa,helminth, worm, prion, parasite, or other microbe.

In another aspect, the compounds disclosed can be used as syntheticintermediates in the preparation of bifunctional compounds that causedegradation of a selected protein via the ubiquitin proteosome pathway(UPP) is provided. These compounds contain a functional group that canreact with a second compound, wherein the second compound is capable ofbinding to a selected protein of interest, to create a bifunctionalcompound as described above that can cause the degradation of theselected protein via the UPP.

Thus, compounds of Formula XIV or XV, or a pharmaceutically acceptablesalt thereof, which can be used in the preparation of compounds thatcause degradation of a selected protein via the UPP are provided:

wherein:

X^(A1) is selected from the group consisting of arylene,heterocyclylene, heteroarylene, and C₁₋₆-alkylene;

X^(B1) is selected from the group consisting of arylene andheteroarylene; and

“Tail” is a chemical moiety that contains a reactive functional groupthat can covalently bind to a protein binding moiety to produce atargeted protein degrader, or

“Tail is a chemical moiety that can be used to modify the properties ofthe compound such as hydrophobility, hydrophilicity, solubility, drugdeliver, pharmacokinetic, or other properties such as charge, polarity,or fit within the active pocket;

-   -   in one embodiment, “Tail” is “T”,

wherein “T” is

X¹ is selected from bond, NR³⁴, CH₂, CHR³⁴, C(R³⁴)₂, O, and S;

X²² is a functional group that can be used as a linking group to aprotein binding moiety; or X²² is a group that caps the valence and isnot typically a linking group; representative examples of X²² include,but are not limited to, halo, —NH₂, —NHR³⁴, —N(R³⁴)₂, hydroxyl, thiol,—B(OH)₂, —Sn(R³⁶)₃, —Si(R³⁶)₃, —OS(O)₂alkyl, —OS(O)₂haloalkyl, alkenyl,alkynyl, ethynyl, ethenyl, —C(O)H, —NR³⁴C(O)alkene, —NR³⁴C(O)alkyne,cyano, —SC(O)alkyl, OC(O)alkyl, heterocycle, —C(O)OH, hydrogen, alkyl,aryl, heteroaryl, aliphatic, heteroaliphatic, and carbocyclic;

R³⁴ and R^(34′) are independently selected at each occurrence fromhydrogen, C₁-C₆alkyl (for example methyl, ethyl, cyclopropyl, orC₁-C₃alkyl), C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, C₃-C₆heterocycle, aryl, heteroaryl, —(CO)R³⁶, —(CS)R³⁶,—(C═NH)R³⁶, —(SO)R³⁶, and —(SO₂)R³⁶;

R³⁶ is independently selected at each occurrence from hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,C₃-C₆heterocycle, aryl, heteroaryl, hydroxyl, C₁-C₆alkoxy, thio,C₁-C₆thioalkyl, —NH₂, —NH(C₁-C₆alkyl, C₃-C₇cycloalkyl, C₃-C₇heterocycle,aryl, or heteroaryl), and —N(independently C₁-C₆alkyl, C₃-C₇cycloalkyl,C₃-C₇heterocycle, aryl, or heteroaryl)₂;

R²⁰, R²¹, R²², R²³ and R²⁴ are independently a divalent or multivalentlinking group, including but not limited to a covalent bond, alkyl,—C(O)—, —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —C(S)—, —SO₂—,—S(O)—, —C(S)—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—,—S—, —NH—, —N(alkyl)-, —CH(—O—R²⁶)—, —CH(—NR³⁴R^(34′))—,—C(—O—R²⁶)alkyl-, —C(—NR³⁴R^(34′))alkyl-, —C(R⁴⁰R⁴⁰)—,-alkyl(R²⁷)-alkyl(R²⁸)—, —C(R²⁷R²⁸)—, —P(O)(OR²⁶)O—, —P(O)(OR²⁶)—,—NR³⁴C(O)NR^(34′)—, alkene, haloalkyl, alkoxy, alkyneheteroarylalkyl,aryl, arylalkyl, heterocycle, aliphatic, heteroaliphatic, heteroaryl,lactic acid, glycolic acid, carbocycle, -(ethylene glycol)1-6-,-(lactic-co-glycolic acid)1-6-, -(propylene glycol)1-6-,—O—(CH₂)₁₋₁₂-O—, —NH—(CH₂)₁₋₁₂—NH—, —NH—(CH₂)₁₋₁₂—O—, —O—(CH₂)₁₋₁₂—NH—,—S—(CH₂)₁₋₁₂—O—, —O—(CH₂)₁₋₁₂—S—, —S—(CH₂)₁₋₁₂—S—, —S—(CH₂)₁₋₁₂—NH—, and—NH—(CH₂)₁₋₁₂—S—, wherein the 1-6 can be independently 1, 2, 3, 4, 5, or6, wherein the 1-12 can be independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12, and wherein one or more of the CH₂ or NH groups can bemodified by substitution of a H for a methyl, ethyl, cyclopropyl, F (ifon carbon), etc, as described herein, and optionally, a heteroatom,heteroalkyl, aryl, heteroaryl or cycloaliphatic group is interspersed inthe chain. Certain non-limiting examples include—O—CH(CH₃)—CH(CH₃)CH—O—, —O—CH₂—CH(CH₃)CH—O—, —O—CH(CH₃)—CH₂CH—O—, etc.,

each of which R²⁰, R²¹, R²², R²³, and R²⁴ is optionally substituted withone or more substituents selected from R¹⁰¹ or alternatively asdescribed in the Definitions section; wherein at least one of R²⁰, R²¹,R²², R²³, and R²⁴ is not a bond;

R¹⁰¹ is independently selected at each occurrence from hydrogen, alkyl,alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl,heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy,heteroaryloxy, CN, —COOalkyl, COOH, NO₂, F, Cl, Br, I, CF₃, NH₂,NHalkyl, N(alkyl)₂, aliphatic, and heteroaliphatic;

R²⁶ is selected from hydrogen, alkyl, silane, arylalkyl,heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic,aliphatic and heteroaliphatic;

R²⁷ and R²⁸ are independently selected from hydrogen, alkyl, and amine,or together with the carbon atom to which they are attached, form C(O),C(S), C═CH₂, a C₃-C₆ spirocarbocycle, or a 4-, 5-, or 6-memberedspiroheterocycle comprising 1 or 2 heteroatoms selected from N and O, orform a 1 or 2 carbon bridged ring;

R⁴⁰ is selected at each instance from: hydrogen, alkyl, alkene, alkyne,halogen, hydroxyl, alkoxy, azide, amino, cyano, —NH(aliphatic, includingalkyl), —N(aliphatic, including alkyl)₂, —NHSO₂(aliphatic, includingalkyl), —N(aliphatic, including alkyl)SO₂alkyl, —NHSO₂(aryl, heteroarylor heterocyclic), —N(alkyl)SO₂(aryl, heteroaryl or heterocyclic)—NHSO₂alkenyl, —N(alkyl)SO₂alkenyl, —NHSO₂alkynyl, —N(alkyl)SO₂alkynyl,haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl,heterocyclic, and carbocyclic; and

all other variables are as defined herein.

In one aspect, a compound is provided of one of the following formulas:

or a pharmaceutically acceptable salt thereof;

wherein T is

and all other variables are as defined herein.

In another aspect, a compound is provided of one of the followingformulas:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

In a first aspect, the present invention provides compounds of FormulaIa, Formula Ib, Formula II, Formula IIIa, Formula IIIb, Formula IV,Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X,Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, FormulaXIV-a to XIV-x, and Formula XV-a to XV-t as defined herein for use as atherapeutically active substance.

In a further aspect, the present invention provides pharmaceuticalcompositions comprising a compound of Formula Ia, Formula Ib, FormulaII, Formula IIIa, Formula IIIb, Formula IV, Formula V, Formula VI,Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, FormulaXII, Formula XIII, Formula XIV, Formula XV, Formula XIV-a to XIV-x, andFormula XV-a to XV-t as defined herein and a therapeutically inertcarrier.

In certain embodiments, the compound of Formula Ia, Formula Ib, FormulaII, Formula IIIa, Formula IIIb, Formula IV, Formula V, Formula VI,Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, FormulaXII, Formula XIII, Formula XIV, Formula XV, Formula XIV-a to XIV-x, andFormula XV-a to XV-t has at least one desired isotopic substitution ofan atom, at an amount above the natural abundance of the isotope, i. e.,enriched. In one embodiment, the compound of Formula Ia, Formula Ib,Formula II, Formula IIIa, Formula IIIb, Formula IV, Formula V, FormulaVI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI,Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XIV-a toXIV-x, and Formula XV-a to XV-t includes a deuterium or multipledeuterium atoms.

The present compounds are useful for the therapeutic and/or prophylactictreatment of cancer.

The compounds of the present invention can further be used as part ofbifunctional compounds that comprise the compounds of present inventionas E3 Ubiquitin Ligase moiety that is linked to a moiety that binds to atarget protein where the target protein is proximate to the ubiquitinligase to effect degradation of said protein.

Other features and advantages of the present application will beapparent from the following detailed description and claims.

The present invention therefore includes at least the followingfeatures:

-   -   a) a compound of Formula Ia, Formula Ib, Formula II, Formula        IIIa, Formula IIIb, Formula IV, Formula V, Formula VI, Formula        VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula        XIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-t        or a pharmaceutically acceptable salt thereof;    -   b) use of a compound of Formula Ia, Formula Ib, Formula II,        Formula IIIa, Formula IIIb, Formula IV, Formula V, Formula VI,        Formula VII, Formula VIII, Formula IX, Formula X, Formula XI,        Formula XII, Formula XIII, Formula XIV, Formula XV, Formula        XIV-a to XIV-x, or Formula XV-a to XV-t or a pharmaceutically        acceptable salt thereof, in an effective amount in the treatment        of a patient, typically a human, with a disorder that responds        to such treatment, including by modulating the cereblon-based        ubiquitination of a protein, such as for example, abnormal        cellular proliferation such as a tumor or cancer, an immune or        autoimmune or inflammatory disorder, a cardiologic disorder, an        infectious disease, or other disorder that responds to such        treatment;    -   c) use of a compound of Formula Ia, Formula Ib, Formula II,        Formula IIIa, Formula IIIb, Formula IV, Formula V, Formula VI,        Formula VII, Formula VIII, Formula IX, Formula X, Formula XI,        Formula XII, Formula XIII, Formula XIV, Formula XV, Formula        XIV-a to XIV-x, or Formula XV-a to XV-t or a pharmaceutically        acceptable salt thereof, in the manufacture of a medicament for        the treatment of a medical disorder, as further described        herein;    -   d) a method for manufacturing a medicament intended for the        therapeutic treatment of a disorder in a host, characterized in        that a compound of Formula Ia, Formula Ib, Formula II, Formula        IIIa, Formula IIIb, Formula IV, Formula V, Formula VI, Formula        VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula        XII, Formula XIII, Formula XIV, Formula XV, Formula XIV-a to        XIV-x, or Formula XV-a to XV-t is used in the manufacture;    -   e) a compound of Formula Ia, Formula Ib, Formula II, Formula        IIIa, Formula IIIb, Formula IV, Formula V, Formula VI, Formula        VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula        XII, Formula XIII, Formula XIV, Formula XV, Formula XIV-a to        XIV-x, or Formula XV-a to XV-t or a pharmaceutically acceptable        salt thereof, that are useful in the treatment of an abnormal        cellular proliferation such as cancer in a host, including any        of the cancers described herein;    -   f) use of a compound of Formula Ia, Formula Ib, Formula II,        Formula IIIa, Formula IIIb, Formula IV, Formula V, Formula VI,        Formula VII, Formula VIII, Formula IX, Formula X, Formula XI,        Formula XII, Formula XIII, Formula XIV, Formula XV, Formula        XIV-a to XIV-x, and Formula XV-a to XV-t, or a pharmaceutically        acceptable salt thereof, in the manufacture of a medicament for        the treatment of an abnormal cellular proliferation such as        cancer, including any of the cancers described herein;    -   g) a method for manufacturing a medicament intended for the        therapeutic use of treating an abnormal cellular proliferation        such as cancer in a host, including any of the cancers described        herein, characterized in that a compound of Formula Ia, Formula        Ib, Formula II, Formula IIIa, Formula IIIb, Formula IV, Formula        V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X,        Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV,        Formula XIV-a to XIV-x, or Formula XV-a to XV-t is used in the        manufacture;    -   h) a compound of Formula Ia, Formula Ib, Formula II, Formula        IIIa, Formula IIIb, Formula IV, Formula V, Formula VI, Formula        VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula        XII, Formula XIII, Formula XIV, Formula XV, Formula XIV-a to        XIV-x, or Formula XV-a to XV-t or a pharmaceutically acceptable        salt thereof, that is useful in the treatment of a tumor in a        host, including any of the tumors described herein;    -   i) use of a compound of Formula Ia, Formula Ib, Formula II,        Formula IIIa, Formula IIIb, Formula IV, Formula V, Formula VI,        Formula VII, Formula VIII, Formula IX, Formula X, Formula XI,        Formula XII, Formula XIII, Formula XIV, Formula XV, Formula        XIV-a to XIV-x, or Formula XV-a to XV-t or a pharmaceutically        acceptable salt thereof, in the manufacture of a medicament for        the treatment of a tumor in a host, including any of the tumors        described herein;    -   j) a method for manufacturing a medicament intended for the        therapeutic use of treating a tumor in a host, including any of        the tumors described herein, characterized in that a compound of        Formula Ia, Formula Ib, Formula II, Formula IIIa, Formula IIIb,        Formula IV, Formula V, Formula VI, Formula VII, Formula VIII,        Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,        Formula XIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a        to XV-t is used in the manufacture;    -   k) a compound of Formula Ia, Formula Ib, Formula II, Formula        IIIa, Formula IIIb, Formula IV, Formula V, Formula VI, Formula        VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula        XII, Formula XIII, Formula XIV, Formula XV, Formula XIV-a to        XIV-x, or Formula XV-a to XV-t or a pharmaceutically acceptable        salt thereof, that is useful in the treatment of an immune,        autoimmune, or inflammatory disorder in a host;    -   l) use of a compound of Formula Ia, Formula Ib, Formula II,        Formula IIIa, Formula IIIb, Formula IV, Formula V, Formula VI,        Formula VII, Formula VIII, Formula IX, Formula X, Formula XI,        Formula XII, Formula XIII, Formula XIV, Formula XV, Formula        XIV-a to XIV-x, or Formula XV-a to XV-t or a pharmaceutically        acceptable salt thereof, in the manufacture of a medicament for        the treatment of an immune, autoimmune, or inflammatory disorder        in a host;    -   m) a method for manufacturing a medicament intended for the        therapeutic use of treating an immune, autoimmune, or        inflammatory disorder in a host, characterized in that a        compound of Formula Ia, Formula Ib, Formula II, Formula IIIa,        Formula IIIb, Formula IV, Formula V, Formula VI, Formula VII,        Formula VIII, Formula IX, Formula X, Formula XI, Formula XII,        Formula XIII, Formula XIV, Formula XV, Formula XIV-a to XIV-x,        or Formula XV-a to XV-t is used in the manufacture;    -   n) a pharmaceutical formulation comprising an effective        host-treating amount of a compound of a compound of Formula Ia,        Formula Ib, Formula II, Formula IIIa, Formula IIIb, Formula IV,        Formula V, Formula VI, Formula VII, Formula VIII, Formula IX,        Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV,        Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-t or a        pharmaceutically acceptable salt thereof, with a        pharmaceutically acceptable carrier or diluent;    -   o) a compound of Formula Ia, Formula Ib, Formula II, Formula        IIIa, Formula IIIb, Formula IV, Formula V, Formula VI, Formula        VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula        XII, Formula XIII, Formula XIV, Formula XV, Formula XIV-a to        XIV-x, or Formula XV-a to XV-t as described herein in        enantiomerically or diastereomerically (as relevant) enriched        form, including an isolated enantiomer or diastereomer (i.e.,        greater than 85, 90, 95, 97, or 99% pure);    -   p) a process for the preparation of therapeutic products that        contain an effective amount of a compound of Formula Ia, Formula        Ib, Formula II, Formula IIIa, Formula IIIb, Formula IV, Formula        V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X,        Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV,        Formula XIV-a to XIV-x, or Formula XV-a to XV-t or a        pharmaceutically acceptable salt thereof; and    -   q) a process for the preparation of a bifunctional compound that        causes degradation of a selected protein via the ubiquitin        proteasome pathway, characterized in that a compound of Formula        XIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-t        is used in the preparation of the bifunctional compound.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this application belongs. In the specification,singular forms also include the plural unless the context clearlydictates otherwise. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent application, suitable methods and materials are described below.All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference. The references citedherein are not admitted to be prior art to the claimed application. Inthe case of conflict, the present specification, including definitions,will control. In addition, the materials, methods, and examples areillustrative only and are not intended to be limiting.

The following definitions of the general terms used in the presentdescription apply irrespectively of whether the terms in question appearalone or in combination with other groups.

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

Compounds are described using standard nomenclature. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The compounds in any of the Formulas described herein may be in the formof a racemate, enantiomer, mixture of enantiomers, diastereomer, mixtureof diastereomers, tautomer, N-oxide, isomer, such as rotamer, as if eachis specifically described unless specifically excluded by context.

The compounds of the present invention may form a solvate with a solvent(including water). Therefore, in one non-limiting embodiment, theinvention includes a solvated form of the compound. The term “solvate”refers to a molecular complex of a compound of the present invention(including a salt thereof) with one or more solvent molecules.Non-limiting examples of solvents are water, ethanol, isopropanol,dimethyl sulfoxide, acetone and other common organic solvents. The term“hydrate” refers to a molecular complex comprising a compound of theinvention and water. Pharmaceutically acceptable solvates in accordancewith the invention include those wherein the solvent may be isotopicallysubstituted, e.g. D₂O, d6-acetone, d₆-DMSO. A solvate can be in a liquidor solid form.

The term “C₁₋₆-alkyl”, alone or in combination with other groups, standsfor a hydrocarbon radical which may be linear or branched, with singleor multiple branching, wherein the alkyl group in general comprises 1 to6 carbon atoms, for example, methyl (Me), ethyl (Et), propyl, isopropyl(i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl(tent-butyl), isopentyl, 2-ethyl-propyl (2-methyl-propyl),1,2-dimethyl-propyl and the like. A specific group is methyl.

The term “heteroaryl” denotes a monovalent heterocyclic mono- orbicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4heteroatoms selected from N, O and S, the remaining ring atoms beingcarbon and in which all rings are aromatic. Examples of heteroarylmoieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl,thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl,pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl,diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl,indolinyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl,benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl,benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl,quinolinyl, isoquinolinyl, dihydroquinolyl, dihydropyrrolopyridinyl,dihydronaphthyridinyl, chromanyl, tetrahydroquinolinyl,dihydrocyclopentapyridinyl quinazolinyl, or quinoxalinyl. Particularexamples are pyridinyl, benzimidazolyl, pyrimidyl, benzothiazolyl,thiazolyl thiazolo[4,5-b]pyridinyl, benzothiazolyl, quinolinyl,oxazolo[4,5-b]pyridinyl, benzoxazolyl, thiazolo[4,5-c]pyridinyl,indazolyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl.

In one embodiment “heteroaryl” is a 5 membered aromatic group containing1, 2, 3, or 4 nitrogen atoms.

Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole,furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole,oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole,and thiatriazole.

Additional non-limiting examples of 5 membered “heteroaryl” groupsinclude:

In one embodiment “heteroaryl” is a 6 membered aromatic group containing1, 2, or 3 nitrogen atoms (i.e. pyridinyl, pyridazinyl, triazinyl,pyrimidinyl, and pyrazinyl).

Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2nitrogen atoms include:

In one embodiment “heteroaryl” is a 9 membered bicyclic aromatic groupcontaining 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of “heteroaryl” groups that are bicyclic includeindole, benzofuran, isoindole, indazole, benzimidazole, azaindole,azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole,benzoisothiazole, benzooxazole, and benzothiazole.

Additional non-limiting examples of “heteroaryl” groups that arebicyclic include:

Additional non-limiting examples of “heteroaryl” groups that arebicyclic include:

Additional non-limiting examples of “heteroaryl” groups that arebicyclic include:

In one embodiment “heteroaryl” is a 10 membered bicyclic aromatic groupcontaining 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of “heteroaryl” groups that are bicyclic includequinoline, isoquinoline, quinoxaline, phthalazine, quinazoline,cinnoline, and naphthyridine.

Additional non-limiting examples of “heteroaryl” groups that arebicyclic include:

In another embodiment “heteroaryl” is “optionally substituted” with 1,2, 3, or 4 subsituents.

The term “heterocycloalkyl” or “heterocyclyl” denotes a monovalentsaturated or partly unsaturated mono- or bicyclic ring system of 4 to 9ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, Oand S, the remaining ring atoms being carbon. Examples for monocyclicsaturated heterocycloalkyl are azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl,thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl,homopiperazinyl, or oxazepanyl. Examples for bicyclic saturatedheterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl,8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl,3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl.Examples for partly unsaturated heterocycloalkyl are dihydrofuryl,imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl.A particular example is indolinyl.

In one embodiment “heterocyclyl” refers to a cyclic ring with onenitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocyclyl” refers to a cyclic ring with onenitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocyclyl” refers to a cyclic ring with twonitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocyclyl” refers to a cyclic ring with one oxygenand 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocyclyl” refers to a cyclic ring with one sulfurand 3, 4, 5, 6, 7, or 8 carbon atoms.

Non-limiting examples of “heterocyclyl” include aziridine, oxirane,thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane.

Additional non-limiting examples of “heterocyclyl” include pyrrolidine,3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

Additional non-limiting examples of “heterocyclyl” includetetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane,and 1,3-oxathiolane.

Additional non-limiting examples of “heterocyclyl” include piperidine,piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane,1,4-dithiane, morpholine, and thiomorpholine.

Non-limiting examples of “heterocyclyl” also include:

Additional non-limiting examples of “heterocyclyl” include:

Additional non-limiting examples of “heterocyclyl” include:

Non-limiting examples of “heterocyclyl” also include:

Non-limiting examples of “heterocyclyl” also include:

Additional non-limiting examples of “heterocyclyl” include:

Additional non-limiting examples of “heterocyclyl” include:

In another embodiment “heterocyclyl” is “optionally substituted” with 1,2, 3, or 4 substituents.

The term “aryl” denotes a monovalent aromatic carbocyclic mono- orbicyclic ring system comprising 6 to 10 carbon ring atoms and in whichat least one ring is aromatic. Examples of aryl moieties include phenyl(Ph), indanyl, 1,2,3,4-tetrahydronaphthalenyl and naphthyl. Particularexamples are phenyl, indanyl and 1,2,3,4-tetrahydronaphthalenyl.

In one embodiment “aryl” is a 6 carbon aromatic group (phenyl).

In one embodiment “aryl” is a 10 carbon aromatic group (napthyl).

In another embodiment “aryl” is “optionally substituted” with 1, 2, 3,or 4 substituents.

The term “optionally substituted” denotes the substitution of a groupherein by a moiety including, but not limited to, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₂ cycloalkyl, C₃-C₁₂ cycloalkenyl, C₁-C₁₂heterocycloalkyl, C₃-C₁₂ heterocycloalkenyl, alkoxy, aryl, aryloxy,heteroaryl, heteroaryloxy, amino, C₁-C₁₀ alkylamino, dialkylamino,arylamino, diarylamino, C₁-C₁₀ alkylsulfonamino, arylsulfonamino, C₁-C₁₀alkylimino, arylimino, alkylsulfonimino, arylsulfonimino, hydroxyl,halo, thio, C₁-C₁₀ alkylthio, arylthio, alkylsulfonyl, arylsulfonyl,acylamino, aminoacyl, aminothioacyl, amidino, guanidine, ureido, cyano,nitro, azido, acyl, thioacyl, acyloxy, carboxyl, and carboxylic ester.

In another embodiment any suitable group may be present on a“substituted” or “optionally substituted” position if indicated thatforms a stable molecule and meets the desired purpose of the inventionand includes, but is not limited to, e.g., halogen (which canindependently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido;alkanoyl (such as a C₂-C₆ alkanoyl group); carboxamide; alkyl,cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkylincluding those having one or more thioether linkages; alkylsulfinyl;alkylsulfonyl groups including those having one or more sulfonyllinkages; aminoalkyl groups including groups having more than one Natoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each ringeither substituted or unsubstituted); arylalkyl having for example, 1 to3 separate or fused rings and from 6 to about 14 or 18 ring carbonatoms, with benzyl being an exemplary arylalkyl group; arylalkoxy, forexample, having 1 to 3 separate or fused rings with benzyloxy being anexemplary arylalkoxy group; or a saturated or partially unsaturatedheterocycle having 1 to 3 separate or fused rings with one or more N, Oor S atoms, or a heteroaryl having 1 to 3 separate or fused rings withone or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl,quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl,thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl,indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, andpyrrolidinyl. Such groups may be further substituted, e.g. with hydroxy,alkyl, alkoxy, halogen and amino. In certain embodiments “optionallysubstituted” includes one or more substituents independently selectedfrom halogen, hydroxyl, amino, cyano, —CHO, —COOH, —CONH₂, alkylincluding C₁-C₆alkyl, alkenyl including C₂-C₆alkenyl, alkynyl includingC₂-C₆alkynyl, —C₁-C₆alkoxy, alkanoyl including C₂-C₆alkanoyl,C₁-C₆alkylester, (mono- and di-C₁-C₆alkylamino)C₀-C₂alkyl, haloalkylincluding C₁-C₆haloalkyl, hydoxyC₁-C₆alkyl, ester, carbamate, urea,sulfonamide, —C₁-C₆alkyl(heterocyclo), C₁-C₆alkyl(heteroaryl),—C₁-C₆alkyl(C₃-C₇cycloalkyl), O—C₁-C₆alkyl(C₃-C₇cycloalkyl), B(OH)₂,phosphate, phosphonate and haloalkoxy including C₁-C₆haloalkoxy. In someembodiments, the suitable group present on a “substituted” or“optionally substituted” is divalent including, but not limited to, oxo(═O), ═S, ═CH₂, etc. The suitable group on a “substituted” or “optionalsubstituted” position may be monovalent, divalent, or trivalent suchthat it forms a stable molecule and meets the desired purpose of theinvention.

In one embodiment a group described herein that can be substituted with1, 2, 3, or 4 substituents is substituted with one substituent.

In one embodiment a group described herein that can be substituted with1, 2, 3, or 4 sub stituents is substituted with two sub stituents.

In one embodiment a group described herein that can be substituted with1, 2, 3, or 4 sub stituents is substituted with three sub stituents.

In one embodiment a group described herein that can be substituted with1, 2, 3, or 4 sub stituents is substituted with four sub stituents.

The term “pharmaceutically acceptable” denotes an attribute of amaterial which is useful in preparing a pharmaceutical composition thatis generally safe, non-toxic, and neither biologically nor otherwiseundesirable and is acceptable for veterinary as well as humanpharmaceutical use.

The term “a pharmaceutically acceptable salt” refers to a salt that issuitable for use in contact with the tissues of humans and animals.Examples of suitable salts with inorganic and organic acids are, but arenot limited to, acetic acid, citric acid, formic acid, fumaric acid,hydrochloric acid, lactic acid, maleic acid, malic acid,methane-sulfonic acid, nitric acid, phosphoric acid, p-toluenesulphonicacid, succinic acid, sulfuric acid (sulphuric acid), tartaric acid,trifluoroacetic acid and the like. Particular acids are formic acid,trifluoroacetic acid and hydrochloric acid. Specific acids arehydrochloric acid, trifluoroacetic acid and fumaric acid.

Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts and the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, conventional non-toxic acid salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like, or using a differentacid that produces the same counterion. Lists of additional suitablesalts may be found, e.g., in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

The terms “pharmaceutically acceptable auxiliary substance” refer tocarriers and auxiliary substances such as diluents or excipients thatare compatible with the other ingredients of the formulation.

The term “pharmaceutical composition” encompasses a product comprisingspecified ingredients in pre-determined amounts or proportions, as wellas any product that results, directly or indirectly, from combiningspecified ingredients in specified amounts. Particularly it encompassesa product comprising one or more active ingredients, and an optionalcarrier comprising inert ingredients, as well as any product thatresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, and other factors.

The term “as defined herein” and “as described herein” when referring toa variable incorporates by reference the broad definition of thevariable as well as particularly, more particularly and mostparticularly definitions, if any.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

The term “aromatic” denotes the conventional idea of aromaticity asdefined in the literature, in particular in IUPAC—Compendium of ChemicalTerminology, 2^(nd) Edition, A. D. McNaught & A. Wilkinson (Eds).Blackwell Scientific Publications, Oxford (1997).

The term “pharmaceutically acceptable excipient” denotes any ingredienthaving no therapeutic activity and being non-toxic such asdisintegrators, binders, fillers, solvents, buffers, tonicity agents,stabilizers, antioxidants, surfactants or lubricants used in formulatingpharmaceutical products.

Whenever a chiral carbon is present in a chemical structure, it isintended that all stereoisomers associated with that chiral carbon areencompassed by the structure as pure stereoisomers as well as mixturesthereof.

Furthermore, the invention includes all optical isomers, i.e.diastereoisomers, diastereomeric mixtures, racemic mixtures, all theircorresponding enantiomers and/or tautomers as well as their solvates ofthe compounds described herein.

The compounds may contain one or more asymmetric centers and cantherefore occur as racemates, racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. Additionalasymmetric centers may be present depending upon the nature of thevarious substituents on the molecule. Each such asymmetric center willindependently produce two optical isomers and it is intended that all ofthe possible optical isomers and diastereomers in mixtures and as pureor partially purified compounds are included within this invention. Thepresent invention is meant to encompass all such isomeric forms of thesecompounds. The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography.

In the embodiments, where optically pure enantiomers are provided,optically pure enantiomer means that the compound contains >90% of thedesired isomer by weight, particularly >95% of the desired isomer byweight, or more particularly >99% of the desired isomer by weight, saidweight percent based upon the total weight of the isomer(s) of thecompound. Chirally pure or chirally enriched compounds may be preparedby chirally selective synthesis or by separation of enantiomers. Theseparation of enantiomers may be carried out on the final product oralternatively on a suitable intermediate.

All separate embodiments may be combined.

The term “treatment” as used herein includes: (1) inhibiting the state,disorder or condition (e.g. arresting, reducing or delaying thedevelopment of the disease, or a relapse thereof in case of maintenancetreatment, of at least one clinical or subclinical symptom thereof);and/or (2) relieving the condition (i.e., causing regression of thestate, disorder or condition or at least one of its clinical orsubclinical symptoms). However, it will be appreciated that when amedicament is administered to a patient to treat a disease, the outcomemay not always be effective treatment.

The term “prophylaxis” as used herein includes: preventing or delayingthe appearance of clinical symptoms of the state, disorder or conditiondeveloping in a mammal and especially a human that may be afflicted withor predisposed to the state, disorder or condition but does not yetexperience or display clinical or subclinical symptoms of the state,disorder or condition.

Isotopic Substitution

The present invention includes compounds of Formula Ia, Formula Ib,Formula II, Formula III a, Formula IIIb, Formula IV, Formula V, FormulaVI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI,Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XIV-a toXIV-x, and Formula XV-a to XV-t with at least one desired isotopicsubstitution of an atom, at an amount above the natural abundance of theisotope, i.e., enriched. Isotopes are atoms having the same atomicnumber but different mass numbers, i.e., the same number of protons buta different number of neutrons.

Examples of isotopes that can be incorporated into compound of theinvention include isotopes of hydrogen, carbon, nitrogen, and oxygensuch as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N and ¹⁷O, ¹⁸O respectively. In onenon-limiting embodiment, isotopically labelled compounds can be used inmetabolic studies (with, for example ¹⁴C), reaction kinetic studies(with, for example ²H or ³H), detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays, or in radioactive treatment of patients. In particular, an ¹⁸Flabeled compound may be particularly desirable for PET or SPECT studies.Isotopically labeled compounds of this invention and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

Isotopic substitutions, for example deuterium substitutions, can bepartial or complete. Partial deuterium substitution means that at leastone hydrogen is substituted with deuterium. In certain embodiments, theisotope is 90, 95, or 99% or more enriched in an isotope at any locationof interest. In one non-limiting embodiment, deuterium is 90, 95, or 99%enriched at a desired location.

In one non-limiting embodiment, the substitution of a hydrogen atom fora deuterium atom can be provided in any compound of Formula Ia, FormulaIb, Formula II, Formula IIIa, Formula IIIb, Formula IV, Formula V,Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, FormulaXI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XIV-a toXIV-x, and Formula XV-a to XV-t. In one non-limiting embodiment, thesubstitution of a hydrogen atom for a deuterium atom occurs within oneor more groups selected from the variables described herein. Forexample, when any of the groups are, or contain for example throughsubstitution, methyl, ethyl, or methoxy, the alkyl residue may bedeuterated (in non-limiting embodiments, CDH₂, CD₂H, CD₃, CH₂CD₃,CD₂CD₃, CHDCH₂D, CHDCHD₂, OCDH₂, OCD₂H, or OCD₃, etc.). In certain otherembodiments, when two substitutions are combined to form a cycle, theunsubstituted carbons may be deuterated.

II. Compounds of the Present Invention

The present invention provides compounds of Formula Ia, Formula Ib,Formula II, Formula IIIa, Formula IIIb, Formula IV, Formula V, FormulaVI, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII,Formula XIV, Formula XV, Formula XIV-a to XIV-x, and Formula XV-a toXV-t, and pharmaceutically acceptable salts thereof. The invention alsoprovides the use of compounds of Formula VII and Formula XIII as furtherdescribed herein.

Compounds of Formula Ia to Formula VI

In one aspect, a compound is provided of Formula Ia or Formula Ib:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

In one embodiment of Formula Ia, a compound is provided of the formula:

In one embodiment of Formula Ia, a compound is provided selected from:

In one embodiment of Formula Ib, a compound is provided selected from:

In one embodiment of Formula Ib, a compound is provided selected from:

In another aspect, a compound is provided of Formula II:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

In one embodiment of Formula II, a compound is provided selected from:

In one embodiment of Formula II, a compound is provided selected from:

In one embodiment of Formula II, a compound is provided selected from:

In one embodiment of Formula II, a compound is provided selected from:

In one embodiment of Formula II, a compound is provided selected from:

In one embodiment of Formula II, a compound is provided selected from:

In one embodiment of Formula II, a compound is provided selected from:

In one embodiment of Formula II, a compound is provided selected from:

In one embodiment of Formula II, a compound is provided selected from:

In one embodiment of Formula II, a compound is provided selected from:

In one embodiment of Formula II, a compound is provided selected from:

In another aspect, a compound is provided of Formula Ma or Formula IIIb:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

In one embodiment of Formula Ma, a compound is provided of the formula:

In one embodiment of Formula Ma, a compound is provided selected from:

In one embodiment of Formula IIIb, a compound is provided of theformula:

In one embodiment of Formula IIIb, a compound is provided selected from:

In another embodiment, a compound of Formula IV is provided:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

In one embodiment of Formula IV, a compound is provided selected from:

In one embodiment of Formula IV, a compound is provided selected from:

In one embodiment of Formula IV, a compound is provided selected from:

In one embodiment of Formula IV, a compound is provided selected from:

In one embodiment of Formula IV, a compound is provided selected from:

In one embodiment of Formula IV, a compound is provided selected from:

In one embodiment of Formula IV, a compound is provided selected from:

In one embodiment of Formula IV, a compound is provided selected from:

In one embodiment of Formula IV, a compound is provided selected from:

In one embodiment of Formula IV, a compound is provided selected from:

In one embodiment of Formula IV, a compound is provided selected from:

In one embodiment of Formula IV, a compound is provided selected from:

In another embodiment, a compound of Formula V or VI is provided:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

In one embodiment of Formula V, a compound is provided selected from:

In one embodiment of Formula V, a compound is provided selected from:

In one embodiment of Formula V, a compound is provided selected from:

In one embodiment of Formula VI, a compound is provided selected from:

In one embodiment of Formula VI, a compound is provided selected from:

In one embodiment of Formula VI, a compound is provided selected from:

In one embodiment, a compound is provided selected from:

In one embodiment, a compound is provided selected from:

In one embodiment, a compound is provided selected from:

Compounds of Formula VII

In another aspect, the use of a compound for the treatment of atherapeutic condition which can be treated by modulating the function oractivity of the cereblon containing E3 Ubiquitin Ligase Protein Complexis provided of Formula VII:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

In one embodiment, the compound of Formula VII for use in the methodsdescribed herein is selected from:

A compound of Formula VII for use in the methods described herein isalso provided in the following enumerated embodiments, all of which maybe separately combined.

-   E1: A compound of formula VII, or a pharmaceutically acceptable salt    thereof, as described herein, wherein-   X^(A) is selected from the group consisting of    -   i.) heteroaryl, in particular pyridinyl, benzimidazolyl,        pyrimidyl, benzothiazolyl or thiazolyl, each individually        substituted by R⁴;    -   ii.) heteroaryl, in particular thiazolo[4,5-b]pyridinyl,        benzothiazolyl, quinolinyl, oxazolo[4,5-b]pyridinyl,        benzoxazolyl, thiazolo[4,5-c]pyridinyl, indazolyl, benzofuranyl        or pyrazolo[1,5-a]pyridinyl,    -   iii.) heterocyclyl, in particular indolinyl,

iv.) heterocyclyl, in particular indolinyl, substituted by R³,

v.) phenyl, indanyl or 1,2,3,4-tetrahydronaphthalenyl, and

vi.) phenyl, substituted by NO₂, —COOCH₃ or —NH—C(═O)—CH₃;

-   Y^(A) is absent or selected from the group consisting of

i.) —C(═O)—;

ii.) —C(═O)—C(H,C₁₋₆-alkyl)-, and

iii.) —C(═O)—CH₂—;

-   R¹ is absent or ═O;-   R² is selected from the group consisting of

i.) —C(═O)—O—C₁₋₆-alkyl, in particular —C(═O)—O—CH₃,

ii.) —NH—C(═O)—C₁₋₆-alkyl, in particular —NH—C(═O)—CH₃, and

iii.) —NO₂;

-   R³ is selected from the group consisting of

i.) —C(═O)—C₁₋₆-alkyl, in particular —C(═O)—CH₃; and

ii.) ═O;

-   R⁴ is selected from the group consisting of

i.) —C₁₋₆-alkyl, in particular CH₃,

ii.) —COOC₁₋₆-alkyl, in particular —COOCH₃ or —COOC(CH₃)₃,

iii.) —NH₂,

iv.) —NH—C(═O)—C₁₋₆-alkyl, in particular —NH—C(═O)—CH₃, and

v.) —NO₂.

-   E2: A compound of formula VII, or a pharmaceutically acceptable salt    thereof, as described herein, wherein-   a) X^(A) is unsubstituted phenyl or phenyl substituted by R² and-   R² is selected from the group consisting of

i.) —C(═O)—O—CH₃,

ii.) —NH—C(═O)—CH₃, and

iii.) —NO₂,

-   b) X^(A) is indanyl or 1,2,3,4-tetrahydronaphthalenyl,-   c) X^(A) is thiazolo[4,5-b]pyridinyl, benzothiazolyl, quinolinyl,    oxazolo[4,5-b]pyridinyl, benzoxazolyl, thiazolo[4,5-c]pyridinyl,    indazolyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl,-   d) X^(A) is pyridinyl, benzimidazolyl, pyrimidyl, benzothiazolyl or    thiazolyl, each individually substituted by R⁴; and-   R⁴ is selected from the group consisting of

i.) —CH₃,

ii.) —COOCH₃ or —COOC(CH₃)₃,

iii.) —NH₂,

iv.) —NH—C(═O)—CH₃, and

v.) —NO₂; or

-   e) X^(A) is unsubstituted indolinyl or indolinyl substituted by R³,    and-   R³ is selected from the group consisting of

i.) —C(═O)—CH₃; and

ii.) ═O.

-   E3: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, selected from the group    consisting of-   2-((R)-1,2,3,4-tetrahydronaphthalene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-((S)-1,2,3,4-tetrahydronaphthalene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-methyl-2,7-diazaspiro[4.5]decane-3,6,8-trione,-   2-(2,3-dihydro-1H-indene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   methyl 6-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)nicotinate,-   2-(5-nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   methyl    2-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)-1H-benzo[d]imidazole-7-carboxylate,-   methyl    2-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)pyrimidine-4-carboxylate,-   2-(1-methyl-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   methyl    2-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)benzo[d]thiazole-6-carboxylate,-   methyl    2-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)thiazole-4-carboxylate,-   methyl    2-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)thiazole-5-carboxylate,-   tert-butyl 6-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)nicotinate,-   methyl 4-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzoate,-   methyl 6-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)picolinate,-   2-(5-nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   N-(3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)acetamide,-   N-(6-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)pyridin-3-yl)acetamide,-   2-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(2-phenylacetyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(3-nitrobenzoyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(thiazolo[4,5-b]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(4-nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(benzo[d]thiazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(quinolin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(6-aminobenzo[d]thiazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(oxazolo[4,5-b]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(benzo[d]oxazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(thiazolo[4,5-c]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(benzo[d]thiazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(4-nitropicolinoyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(2-oxoindoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(benzo[d]thiazole-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(5-nitropyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(2-(pyridin-3-yl)propanoyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(1-acetylindoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-benzoyl-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(1H-indazole-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(5-aminopyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(indoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(indoline-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(1-acetylindoline-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(benzofuran-3-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(benzo[d]oxazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,    and-   2-(indoline-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione.-   E4: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, selected from the group    consisting of-   2-((R)-1,2,3,4-tetrahydronaphthalene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-((S)-1,2,3,4-tetrahydronaphthalene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(2,3-dihydro-1H-indene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   methyl 6-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)nicotinate,-   2-(5-nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   methyl    2-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)-1H-benzo[d]imidazole-7-carboxylate,-   methyl    2-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)pyrimidine-4-carboxylate,-   2-(1-methyl-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   methyl    2-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)benzo[d]thiazole-6-carboxylate,-   methyl    2-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)thiazole-4-carboxylate,-   methyl    2-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)thiazole-5-carboxylate,-   tert-butyl 6-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)nicotinate,-   methyl 4-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzoate,-   methyl 6-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)picolinate,-   2-(5-nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   N-(3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)acetamide,-   N-(6-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)pyridin-3-yl)acetamide,-   2-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(2-phenylacetyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(3-nitrobenzoyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(thiazolo[4,5-b]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(4-nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(benzo[d]thiazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(quinolin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(6-aminobenzo[d]thiazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(oxazolo[4,5-b]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(benzo[d]oxazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(thiazolo[4,5-c]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(benzo[d]thiazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(4-nitropicolinoyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(2-oxoindoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(benzo[d]thiazole-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(5-nitropyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(2-(pyridin-3-yl)propanoyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(1-acetylindoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-benzoyl-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(1H-indazole-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(5-aminopyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(indoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(indoline-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(1-acetylindoline-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(benzofuran-3-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,-   2-(benzo[d]oxazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione,    and-   2-(indoline-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione.-   E5: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is selected from    the group consisting of

i.) H,

ii.) aryl, in particular indanyl or 1,2,3,4-tetrahydronaphthalenyl,

iii.) aryl, in particular phenyl, substituted by R²,

iv.) heterocyclyl, in particular indolinyl,

v.) heterocyclyl, in particular indolinyl, substituted by R³,

vi.) heteroaryl, in particular thiazolo[4,5-b]pyridinyl, benzothiazolyl,quinolinyl, oxazolo[4,5-b]pyridinyl, benzoxazolyl,thiazolo[4,5-c]pyridinyl, indazolyl, benzofuranyl orpyrazolo[1,5-a]pyridinyl,

vii.) heteroaryl, in particular pyridinyl, benzimidazolyl, pyrimidyl,benzothiazolyl or thiazolyl, each individually substituted by R⁴, and

viii.) C1-6-alkyl, in particular methyl.

-   E6: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is selected from    the group consisting of

i.) H,

ii.) phenyl, indanyl or 1,2,3,4-tetrahydronaphthalenyl,

iii.) phenyl, substituted by R²,

iv.) indolinyl,

v.) indolinyl, substituted by R³,

vi.) thiazolo[4,5-b]pyridinyl, benzothiazolyl, quinolinyl,oxazolo[4,5-b]pyridinyl, benzoxazolyl, thiazolo[4,5-c]pyridinyl,indazolyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl,

vii.) pyridinyl, benzimidazolyl, pyrimidyl, benzothiazolyl or thiazolyl,each individually substituted by R⁴, and

viii.) methyl.

-   E7: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is selected from    the group consisting of

i.) aryl, in particular phenyl, indanyl or1,2,3,4-tetrahydronaphthalenyl,

ii.) aryl, in particular phenyl, substituted by R²,

iii.) heterocyclyl, in particular indolinyl,

iv.) heterocyclyl, in particular indolinyl, substituted by R³,

v.) heteroaryl, in particular thiazolo[4,5-b]pyridinyl, benzothiazolyl,quinolinyl, oxazolo[4,5-b]pyridinyl, benzoxazolyl,thiazolo[4,5-c]pyridinyl, indazolyl, benzofuranyl orpyrazolo[1,5-a]pyridinyl, and

vi.) heteroaryl, in particular pyridinyl, benzimidazolyl, pyrimidyl,benzothiazolyl or thiazolyl, each individually substituted by R⁴.

-   E8: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is selected from    the group consisting of

i.) phenyl, indanyl or 1,2,3,4-tetrahydronaphthalenyl,

ii.) phenyl, substituted by R²,

iii.) indolinyl,

iv.) indolinyl, substituted by R³,

v.) thiazolo[4,5-b]pyridinyl, benzothiazolyl, quinolinyl,oxazolo[4,5-b]pyridinyl, benzoxazolyl, thiazolo[4,5-c]pyridinyl,indazolyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl, and

vi.) pyridinyl, benzimidazolyl, pyrimidyl, benzothiazolyl or thiazolyl,each individually substituted by R⁴.

-   E9: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is H.-   E10: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is aryl.-   E11: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is phenyl, indanyl    or 1,2,3,4-tetrahydronaphthalenyl.-   E12: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is phenyl.-   E13: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is indanyl.-   E14: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is    1,2,3,4-tetrahydronaphthalenyl.-   E15: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is aryl    substituted by R².-   E16: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is phenyl    substituted by R².-   E17: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is heterocyclyl.-   E18: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is indolinyl.-   E19: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is heterocyclyl    substituted by R³.-   E20: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is indolinyl,    substituted by R³.-   E21: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is heteroaryl.-   E21: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is    thiazolo[4,5-b]pyridinyl, benzothiazolyl, quinolinyl,    oxazolo[4,5-b]pyridinyl, benzoxazolyl, thiazolo[4,5-c]pyridinyl,    indazolyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl-   E23: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is heteroaryl    substituted by R⁴.-   E24: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is pyridinyl,    benzimidazolyl, pyrimidyl, benzothiazolyl or thiazolyl, each    individually substituted by R⁴-   E25: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is C₁₋₆-alkyl.-   E26: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(A) is methyl.-   E27: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein Y^(A) is selected from    the group consisting of

i.) —C(═O)—;

ii.) —C(═O)—C(H,C₁₋₆-alkyl)-, in particular —C(═O)—C(H,CH₃)—, and

iii.) —C(═O)—CH₂—.

-   E28: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein Y^(A) is selected from    the group consisting of

i.) —C(═O)—;

ii.) —C(═O)-C(H,CH₃)—, and

iii.) —C(═O)—CH₂—.

-   E29: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein Y^(A) is —C(═O)—.-   E30: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein Y^(A) is    —C(═O)-C(H,C₁₋₆-alkyl)-.-   E31: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein Y^(A) is    —C(═O)—C(H,CH₃)—.-   E32: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein Y^(A) is —C(═O)—CH₂—.-   E33: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein le is absent.-   E34: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R¹ is ═O.-   E35: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R² is selected from the    group consisting of

i.) —C(═O)—O—C₁₋₆-alkyl, in particular —C(═O)—O—CH₃,

ii.) —NH—C(═O)—C₁₋₆-alkyl, in particular —NH—C(═O)—CH₃,

iii.) —NH₂,

iv.) —OH, and

v.) —NO₂.

-   E36: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R² is selected from the    group consisting of

i.) —C(═O)—O—C₁₋₆-alkyl, in particular —C(═O)—O—CH₃,

ii.) —NH—C(═O)—C₁₋₆-alkyl, in particular —NH—C(═O)—CH₃, and

iii.) —NO₂.

-   E37: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R² is selected from the    group consisting of

i.) —C(═O)—O—CH₃,

ii.) —NH—C(═O)—CH₃, and

iii.) —NO₂.

-   E38: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R² is    —C(═O)—O—C₁₋₆-alkyl.-   E39: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R² is —C(═O)—O—CH₃.-   E40: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R² is    —NH—C(═O)—C₁₋₆-alkyl.-   E41: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R² is —NH—C(═O)—CH₃.-   E42: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R² is —NO₂.-   E43: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R³ is selected from the    group consisting of

i.) —C(═O)—C₁₋₆-alkyl, in particular —C(═O)—CH₃, and

ii.) ═O.

-   E44: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R³ is selected from the    group consisting of

i.) —C(═O)—CH₃, and

ii.) ═O.

-   E45: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R³ is —C(═O)—C₁₋₆-alkyl.-   E46: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R³ is —C(═O)—CH₃.-   E47: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R³ is =0.-   E48: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R⁴ is selected from the    group consisting of

i.) —C(═O)—O—C₁₋₆-alkyl, in particular —C(═O)—O—CH₃ or —C(═O)—O—C(CH₃)₃,

ii.) C₁₋₆-alkyl, in particular methyl,

iii.) —NH₂,

iv.) —NH—C(═O)—C₁₋₆-alkyl, in particular —NH—C(═O)—CH₃, and

v.) —NO₂.

-   E49: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R⁴ is selected from the    group consisting of

i.) —C(═O)—O—CH₃ or —C(═O)—O—C(CH₃)₃,

ii.) methyl,

iii.) —NH₂,

iv.) —NH—C(═O)—CH₃, and

v.) —NO₂.

-   E50: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R⁴ is    —C(═O)—O—C₁₋₆-alkyl.-   E51: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R⁴ is —C(═O)—O—CH₃.-   E52: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R⁴ is —C(═O)—O—C(CH₃)₃.-   E53: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R⁴ is C₁₋₆-alkyl.-   E54: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R⁴ is methyl.-   E55: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R⁴ is    —NH—C(═O)—C₁₋₆-alkyl.-   E56: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R⁴ is —NH—C(═O)—CH₃.-   E57: The compound of formula VII, or pharmaceutically acceptable    salts thereof, as described herein, wherein R⁴ is —NO₂.-   E58: A certain embodiment of the invention relates to the compound    of formula VII as described herein, or a pharmaceutically acceptable    salt thereof, for use as therapeutically active substance.-   E59: A certain embodiment of the invention relates to the compound    of formula VII as described herein, or a pharmaceutically acceptable    salt thereof, for the use in the therapeutic and/or prophylactic    treatment of cancer.-   E60: A certain embodiment of the invention relates to the compound    of formula VII as described herein, or a pharmaceutically acceptable    salt thereof, for the manufacture of a medicament for the    therapeutic and/or prophylactic treatment of cancer.-   E61: A certain embodiment of the invention relates to a    pharmaceutical composition comprising the compound of formula VII as    described herein, or a pharmaceutically acceptable salt thereof, and    a pharmaceutically acceptable auxiliary substance.-   E62: A certain embodiment of the invention relates to a method for    the therapeutic and/or prophylactic treatment of cancer, by    administering the compound of formula VII as described herein, or a    pharmaceutically acceptable salt thereof, to a patient.

Compounds of Formula VIII to Formula XII

In another aspect, a compound is provided of Formula VIII:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

In one embodiment, a compound of Formula VIII is provided selected from:

In one embodiment, a compound of Formula VIII is provided selected from:

In one embodiment, a compound of Formula VIII is provided selected from:

In another aspect, a compound is provided of Formula IX:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

In one embodiment, a compound of Formula IX is provided selected from:

In another aspect, a compound is provided of Formula X:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

In one embodiment, a compound of Formula X is provided selected from:

In one embodiment, a compound of Formula X is provided selected from:

In one embodiment, a compound of Formula X is provided selected from:

In one embodiment, a compound of Formula X is provided selected from:

In one embodiment, a compound of Formula X is provided selected from:

In another aspect, a compound is provided of Formula XI:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

In one embodiment, a compound of Formula XI is provided selected from:

In one embodiment, a compound of Formula XI is provided selected from:

In one embodiment, a compound of Formula XI is provided selected from:

In one embodiment, a compound of Formula XI is provided selected from:

In another aspect, a compound is provided of Formula XII:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

In one embodiment, a compound of Formula XII is of the formula:

In one embodiment, a compound of Formula XII is provided selected from:

In one embodiment, a compound is provided of the formula

In one embodiment, a compound is provided selected from:

In one embodiment, a compound is provided selected from:

In one embodiment, a compound is provided selected from:

In one embodiment, a compound is provided selected from:

In one embodiment, a compound is provided selected from:

In one embodiment, a compound is provided selected from:

In one embodiment, a compound is provided selected from:

Compounds of Formula XIII

In another aspect, the use of a compound for the treatment of atherapeutic condition which can be treated by modulating the function oractivity of the cereblon containing E3 Ubiquitin Ligase Protein Complexis provided of Formula XIII:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

In one embodiment, a compound of Formula XIII for use in the methodsprovided herein is selected from:

A compound of Formula XIII for use in the methods described herein isalso provided in the following enumerated embodiments, all of which maybe separately combined.

-   E1: A compound of formula XIII, or a pharmaceutically acceptable    salt thereof, as described herein, wherein

X^(B) is selected from the group consisting of

i.) aryl, in particular 1,2,3,4-tetrahydronaphthalenyl or phenyl,

ii.) phenyl substituted by R⁶,

iii.) heteroaryl, in particular benzo[d]thiazolyl,thiazolo[4,5-b]pyridinyl, benzofuranyl or pyrazolo[1,5-a]pyridinyl,

iv.) pyridinyl substituted by R⁷;

R⁶ is selected from the group consisting of

i.) —NH—C(═O)—C₁₋₆-alkyl, in particular —NH—C(═O)—CH₃, and

ii.) —NO₂;

R⁷ is selected from the group consisting of

i.) —C(═O)—O—C₁₋₆-alkyl, in particular —C(═O)—O—CH₃, and

ii.) —NO₂.

-   E2: A compound of formula XIII, or a pharmaceutically acceptable    salt thereof, as described herein, wherein A is NH.-   E3: A compound of formula XIII, or a pharmaceutically acceptable    salt thereof, as described herein, wherein A is CH₂.-   E4: A compound of formula XIII, or a pharmaceutically acceptable    salt thereof, as described herein, wherein Y^(B) is absent.-   E5: A compound of formula XIII, or a pharmaceutically acceptable    salt thereof, as described herein, wherein Y^(B) is —C(═O)—.-   E6: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, selected from the group    consisting of-   (S)-8-(1,2,3,4-tetrahydronaphthalene-1-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione,-   (R)-8-(1,2,3,4-tetrahydronaphthalene-1-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione,-   (S)-8-(1,2,3,4-tetrahydronaphthalene-1-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,-   (R)-8-(1,2,3,4-tetrahydronaphthalene-1-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,-   8-benzoyl-1,3,8-triazaspiro[4.5]decane-2,4-dione,-   8-(benzo[d]thiazol-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,-   8-(thiazolo[4,5-b]pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,-   methyl 6-(2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)nicotinate,-   N-(4-(2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl)phenyl)acetamide,-   N-(3-(2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl)phenyl)acetamide,-   8-(benzofuran-3-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,-   8-(pyrazolo[1,5-a]pyridine-3-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,-   8-(5-nitropyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,-   8-(4-nitrophenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,-   8-(benzo[d]thiazole-5-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,-   8-(thiazolo[4,5-b]pyridin-2-yl)-2,8-diazaspiro[4.5]decane-1,3-dione,-   8-(5-nitropyridin-2-yl)-2,8-diazaspiro[4.5]decane-1,3-dione,-   8-(benzo[d]thiazol-2-yl)-2,8-diazaspiro[4.5]decane-1,3-dione,-   8-(4-nitrophenyl)-2,8-diazaspiro[4.5]decane-1,3-dione,-   8-benzoyl-2,8-diazaspiro[4.5]decane-1,3-dione,-   8-(benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione,-   8-(benzofuran-3-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione,-   methyl 6-(1,3-dioxo-2,8-diazaspiro[4.5]decan-8-yl)nicotinate, and-   8-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione.-   E7: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is selected from    the group consisting of

ix.) 1,2,3,4-tetrahydronaphthalenyl or phenyl,

x.) phenyl substituted by R⁶, wherein R⁶ is —NH—C(═O)—CH₃ or —NO₂,

xi.) benzo[d]thiazolyl, thiazolo[4,5-b]pyridinyl, benzofuranyl orpyrazolo[1,5-a]pyridinyl, and

xii.) pyridinyl substituted by R⁷, wherein R⁷ is —C(═O)—O—CH₃ or —NO₂.

-   E8: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is aryl.-   E9: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is phenyl.-   E10: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is    1,2,3,4-tetrahydronaphthalenyl.

El 1: The compound of formula XIII, or pharmaceutically acceptable saltsthereof, as described herein, wherein X^(B) is aryl substituted by R⁶.

-   E12: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is phenyl    substituted by —NH—C(═O)—CH₃ or —NO₂.-   E13: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is phenyl    substituted by —NH—C(═O)—CH₃.-   E14: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is phenyl    substituted by —NO₂.-   E15: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is heteroaryl.-   E16: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is    benzo[d]thiazolyl, thiazolo[4,5-b]pyridinyl, benzofuranyl or    pyrazolo[1,5-a]pyridinyl-   E17: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is    benzo[d]thiazolyl.-   E18: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is    thiazolo[4,5-b]pyridinyl.-   E19: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is benzofuranyl.-   E20: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is    pyrazolo[1,5-a]pyridinyl.-   E21: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is heteroaryl    substituted by R⁷.-   E22: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is pyridinyl    substituted by —C(═O)—O—CH₃ or —NO₂.-   E23: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is pyridinyl    substituted by —C(═O)—O—CH₃.-   E25: The compound of formula XIII, or pharmaceutically acceptable    salts thereof, as described herein, wherein X^(B) is pyridinyl    substituted by —NO₂.-   E26: A certain embodiment of the invention relates to the compound    of formula XIII as described herein, or a pharmaceutically    acceptable salt thereof, for use as therapeutically active sub    stance.-   E27: A certain embodiment of the invention relates to the compound    of formula XIII as described herein, or a pharmaceutically    acceptable salt thereof, for the use in the therapeutic and/or    prophylactic treatment of cancer.-   E28: A certain embodiment of the invention relates to the compound    of formula XIII as described herein, or a pharmaceutically    acceptable salt thereof, for the manufacture of a medicament for the    therapeutic and/or prophylactic treatment of cancer.-   E29: A certain embodiment of the invention relates to a    pharmaceutical composition comprising the compound of formula XIII    as described herein, or a pharmaceutically acceptable salt thereof,    and a pharmaceutically acceptable auxiliary substance.-   E30: A certain embodiment of the invention relates to a method for    the therapeutic and/or prophylactic treatment of cancer, by    administering the compound of formula XIII as described herein, or a    pharmaceutically acceptable salt thereof, to a patient.

Compounds of Formula XIV or XV

In one aspect, compounds of Formula XIV or XV, or a pharmaceuticallyacceptable salt thereof, are provided:

In one embodiment, a compound of Formula XIV is provided selected from:

In one embodiment, a compound of Formula XV is provided selected from:

In one embodiment, a compound is provided of Formula XIV-a:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-a:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-a or XV-a,

is selected from:

In one embodiment, a compound is provided of Formula XIV-b:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-b:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-b or XV-b,

is selected from:

In one embodiment, a compound is provided of Formula XIV-c:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-c:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-c or XV-c,

is selected from:

In one embodiment, a compound is provided of Formula XIV-d:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-d:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-d or XV-d,

is selected from:

In one embodiment, a compound is provided of Formula XIV-e:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-e:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-e or XV-e,

is selected from:

In one embodiment, a compound is provided of Formula XIV-f:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-f:

wherein all variables are as defined herein.

In some embodiments or XIV-f or XV-f,

is selected from:

In one embodiment, a compound is provided of Formula XIV-g:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-g:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-g or XV-g,

is selected from:

In one embodiment, a compound is provided of Formula XIV-h:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-h:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-h or XV-h,

is selected from:

In one embodiment, a compound is provided of Formula XIV-i:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-i:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-i or XV-i,

is selected from:

In one embodiment, a compound is provided of Formula XIV-j:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-j:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-j or XVj,

is selected from:

In one embodiment, a compound is provided of Formula XIV-k:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-k:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-k or XV-k,

is selected from:

In one embodiment, a compound is provided of Formula XIV-l:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-l:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-l or XV-l,

is selected from:

In one embodiment, a compound is provided of Formula XIV-m:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-m:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-m or XV-m,

is selected from:

In one embodiment, a compound is provided of Formula XIV-n:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-n:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-n or XV-n,

is selected from:

In one embodiment, a compound is provided of Formula XIV-o:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-o:

wherein all variables are as defined herein.

In some embodiments of XIV-o or XV-o,

is selected from:

In one embodiment, a compound is provided of Formula XIV-p:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-p:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-p or XV-p,

is selected from:

In one embodiment, a compound is provided of Formula XIV-q:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-q:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-q or XV-q,

is selected from:

In one embodiment, a compound is provided of Formula XIV-r:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-r:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-r or XV-r,

is selected from:

In one embodiment, a compound is provided of Formula XIV-s:

Wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-s:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-s or XV-s,

is selected from:

In one embodiment, a compound is provided of Formula XIV-t:

wherein all variables are as defined herein.

In one embodiment, a compound is provided of Formula XV-t:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-t or XV-t,

is selected from:

In one embodiment, a compound is provided of Formula XIV-u:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-u,

is selected from:

In one embodiment, a compound is provided of Formula XIV-v:

wherein all variables are as defined herein.

In some embodiments of Formla XIV-v,

is selected from:

In one embodiment, a compound is provided of Formula XIV-w:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-w,

is selected from:

In one embodiment, a compound is provided of Formula XIV-x:

wherein all variables are as defined herein.

In some embodiments of Formula XIV-x,

is selected from:

III. Tail Embodiments

In one embodiment, “Tail” is a moiety selected from Formula T-I, FormulaT-II, Formula T-III, Formula T-IV, Formula T-V, Formula T-VI, andFormula T-VII:

wherein all variables are defined as above.

In an additional embodiment, “Tail” is a moiety selected from FormulaT-VIII, T-IX, and T-X:

wherein all variables are defined as above. In other embodiments ofT-VIII, T-IX and T-X, a carbocyclic ring is used in place of theheterocycle.

The following are non-limiting examples of “Tail” moieties that can beused in this invention. Based on this elaboration, those of skill in theart will understand how to use the full breadth of “Tail” moieties thatwill accomplish the goal of the invention.

As certain non-limiting examples, Formula T-I, Formula T-II, FormulaT-III, Formula T-IV, Formula T-V, Formula T-VI, or Formula T-VIIinclude:

In an additional embodiment “Tail” is selected from:

In an additional embodiment “Tail” is selected from:

Non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, and R²⁴include:

Additional non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, andR²⁴ include:

Additional non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, andR²⁴ include:

In additional embodiments, “Tail” is an optionally substituted ethyleneglycol having at least 1, at least 2, at least 3, at least 4, at least5, at least 6, at least 7, at least 8, at least 9, at least 10, ethyleneglycol units, or optionally substituted alkyl groups interspersed withoptionally substituted, O, N, S, P or Si atoms. In certain embodiments,“Tail” is flanked, substituted, or interspersed with an aryl, phenyl,benzyl, alkyl, alkylene, or heterocycle group. In certain embodiments,“Tail” may be asymmetric or symmetrical. In some embodiments, “Tail” isa substituted or unsubstituted polyethylene glycol group ranging in sizefrom about 1 to about 12 ethylene glycol units, between 1 and about 10ethylene glycol units, about 2 about 6 ethylene glycol units, betweenabout 2 and 5 ethylene glycol units, between about 2 and 4 ethyleneglycol units. In any of the embodiments of the compounds describedherein, “Tail” group may be any suitable moiety as described herein.

In additional embodiments, the “Tail” is selected from:

-   —NR⁶¹(CH₂)_(n1)-(lower alkyl)-X²², —NR⁶¹(CH₂)_(n1)-(lower    alkoxyl)-X²²,-   —NR⁶¹(CH₂)_(n1)-(lower alkoxyl)-OCH₂—X²², —NR⁶¹(CH₂)_(n1)-(lower    alkoxyl)-(lower alkyl)-OCH₂—X²²,-   —NR⁶¹(CH₂)_(n1)-(cycloalkyl)-(lower alkyl)-OCH₂—X²²,    —NR⁶¹(CH₂)_(n1)-(heterocycloalkyl)-X²²,-   —NR⁶¹(CH₂CH₂O)_(n1)-(lower alkyl)-O—CH₂—X²²,-   —NR⁶¹(CH₂CH₂O)_(n1)-(heterocycloalkyl)-O—CH₂—X²²,-   —NR⁶¹(CH₂CH₂O)_(n1)-A-Aryl-O—CH₂—X²²,    —NR⁶¹(CH₂CH₂O)_(n1)-(heteroaryl)-O—CH₂—X²²,-   —NR⁶¹(CH₂CH₂O)_(n1)-(cycloalkyl)-O-(heteroaryl)-O—CH₂—X²²,-   —NR⁶¹(CH₂CH₂O)_(n1)-(cycloalkyl)-O-Aryl-O—CH₂—X²²,-   —NR⁶¹(CH₂CH₂O)_(n1)-(lower alkyl)-NH-Aryl-O—CH₂—X²²,-   —NR⁶¹(CH₂CH₂O)_(n1)-(lower alkyl)-O-Aryl-CH₂—X²²,-   —NR⁶¹(CH₂CH₂O)_(n1)-cycloalkyl-O-Aryl-X²²,    —NR⁶¹(CH₂CH₂O)_(n1)-cycloalkyl-O-heteroaryl-X²²,-   —NR⁶¹(CH₂CH₂)_(n1)-(cycloalkyl)-O-(heterocycle)-CH₂—X²²-   —NR⁶¹(CH₂CH₂)_(n1)-(heterocycle)-(heterocycle)-CH₂—X²², and    —NR⁶¹-(heterocycle)-CH₂—X²²;-   wherein n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   R⁶¹ is H, methyl, or ethyl.

In additional embodiments, “Tail” is selected from:

-   —N(R⁶¹)—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OCH₂—X²²,-   —O—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OCH₂—X²²,-   —O—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OH;-   —N(R⁶¹)—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OH;-   —(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OH;-   —(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OCH₂—X²²;-   —O(CH₂)_(m1)O(CH₂)_(n2)O(CH₂)_(p1)O(CH₂)_(q1)OCH₂—X²²;-   —O(CH₂)_(m1)O(CH₂)_(n2)O(CH₂)_(p1)O(CH₂)_(q1)OCH₂—X²²; wherein-   m1, n2, o1, p1, q1, and r1 are independently 1, 2, 3, 4, or 5; and-   R⁶¹ is H, methyl, or ethyl.

In additional embodiments, “Tail” is selected from:

m1, n2, o1, p1, q2, and r1 are independently 1, 2, 3, 4, or 5.

In additional embodiments, “Tail” is selected from:

In additional embodiments, “Tail” is selected from:

In additional embodiments, “Tail” is selected from:

wherein R⁷¹ is —O—, —NH, Nalkyl, heteroaliphatic, aliphatic, or —NMe.

In additional embodiments, “Tail” is selected from:

In additional embodiments, “Tail” is selected from:

In additional embodiments, “Tail” is selected from:

In additional embodiments, “Tail” is selected from:

In additional embodiments, “Tail” is selected from:

In the above embodiments X²² is selected such that a compoundsufficiently stable or the intended use results.

In additional embodiments, “Tail” is selected from:

In certain embodiments, “Tail” is selected from:

In certain embodiments “Tail” is selected from:

In the above structures

represents

In certain embodiments, “Tail” can be a 4-24 carbon atom linear chains,wherein one or more the carbon atoms in the linear chain can be replacedor substituted with oxygen, nitrogen, amide, fluorinated carbon, etc.,such as the following:

In certain embodiments, “Tail” can be a nonlinear chain, and can be, orinclude, aliphatic or aromatic or heteroaromatic cyclic moieties.

In certain embodiments, “Tail” may include contiguous, partiallycontiguous or non-contiguous ethylene glycol unit groups ranging in sizefrom about 1 to about 12 ethylene glycol units, between 1 and about 10ethylene glycol units, about 2 about 6 ethylene glycol units, betweenabout 2 and 5 ethylene glycol units, between about 2 and 4 ethyleneglycol units, for example, 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11 or 12ethylene glycol units.

In certain embodiments, “Tail” may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, or 15 fluorine substituents. In another embodiment“Tail” is perfluorinated. In yet another embodiment “Tail” is apartially or fully fluorinated poly ether. Nonlimiting examples offluorinated “Tail” moieties include:

Representative examples of X²² include:

In certain embodiments, the length can be adjusted as desired or asfound necessary for the desired application.

IV. Methods of Treatment

The compounds of Formula Ia, Formula Ib, Formula II, Formula IIIa,Formula IIIb, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,Formula XIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-tcan be used in an effective amount to treat a host, including a human,in need thereof, optionally in a pharmaceutically acceptable carrier totreat any of the disorders described herein.

The terms “treat”, “treating”, and “treatment”, etc., as used herein,refer to any action providing a benefit to a patient for which thepresent compounds may be administered, including the treatment of anydisease state or condition which is modulated through the protein towhich the present compounds bind. Illustrative non-limiting diseasestates or conditions, including cancer, which may be treated usingcompounds according to the present invention are set forth hereinabove.

The term “disease state or condition” when used in connection with aFormula Ia, Formula Ib, Formula II, Formula IIIa, Formula IIIb, FormulaIV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX,Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, FormulaXV, Formula XIV-a to XIV-x, or Formula XV-a to XV-t compound forexample, refers to any therapeutic indication which can be treated bydecreasing the activity of cereblon or a cereblon-containing E3 Ligase.Nonlimiting examples of uses for cereblon binders are multiple myeloma,a hematological disorder such as myelodysplastic syndrome, cancer,tumor, abnormal cellular proliferation, HIV/AIDS, HBV, HCV, hepatitis,Crohn's disease, sarcoidosis, graft-versus-host disease, rheumatoidarthritis, Behcet's disease, tuberculosis, and myelofibrosis. Otherindications include a myelo- or lymphoproliferative disorder such as B-or T-cell lymphomas, Waldenstrom's macroglobulinemia, Wiskott-Aldrichsyndrome, or a post-transplant lymphoproliferative disorder; an immunedisorder, including autoimmune disorders such as Addison disease, Celiacdisease, dermatomyositis, Graves disease, thyroiditis, multiplesclerosis, pernicious anemia, arthritis, and in particular rheumatoidarthritis, lupus, or type I diabetes; a disease of cardiologicmalfunction, including hypercholesterolemia; an infectious disease,including viral and/or bacterial infection, as described generallyherein; an inflammatory condition, including asthma, chronic pepticulcers, tuberculosis, rheumatoid arthritis, periodontitis and ulcerativecolitis.

In certain embodiments, the present invention provides for administeringa compound of Formula Ia, Formula Ib, Formula II, Formula IIIa, FormulaIIIb, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII,Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, FormulaXIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-t to apatient, for example, a human, having an infectious disease, wherein thetherapy targets a protein of the infectious agent, optionally incombination with another bioactive agent. The disease state or conditionmay be a disease caused by a microbial agent or other exogenous agentsuch as a virus (as non-limiting examples, HIV, HBV, HCV, HSV, HPV, RSV,CMV, Ebola, Flavivirus, Pestivirus, Rotavirus, Influenza, Coronavirus,EBV, viral pneumonia, drug-resistant viruses, Bird flu, RNA virus, DNAvirus, adenovirus, poxvirus, Picornavirus, Togavirus, Orthomyxovirus,Retrovirus or Hepadnovirus), bacteria (Gram-negative, Gram-positive,fungus, protozoa, helminth, worms, prion, parasite, or other microbe ormay be a disease state, which is caused by overexpression of a protein,which leads to a disease state and/or condition.

In certain embodiments, the condition treated with a compound of thepresent invention is a disorder related to abnormal cellularproliferation. Abnormal cellular proliferation, notablyhyperproliferation, can occur as a result of a wide variety of factors,including genetic mutation, infection, exposure to toxins, autoimmunedisorders, and benign or malignant tumor induction.

There are a number of skin disorders associated with cellularhyperproliferation. Psoriasis, for example, is a benign disease of humanskin generally characterized by plaques covered by thickened scales. Thedisease is caused by increased proliferation of epidermal cells ofunknown cause. Chronic eczema is also associated with significanthyperproliferation of the epidermis. Other diseases caused byhyperproliferation of skin cells include atopic dermatitis, lichenplanus, warts, pemphigus vulgaris, actinic keratosis, basal cellcarcinoma and squamous cell carcinoma.

Other hyperproliferative cell disorders include blood vesselproliferation disorders, fibrotic disorders, autoimmune disorders,graft-versus-host rejection, tumors and cancers.

Blood vessel proliferative disorders include angiogenic and vasculogenicdisorders. Proliferation of smooth muscle cells in the course ofdevelopment of plaques in vascular tissue cause, for example,restenosis, retinopathies and atherosclerosis. Both cell migration andcell proliferation play a role in the formation of atheroscleroticlesions.

Fibrotic disorders are often due to the abnormal formation of anextracellular matrix. Examples of fibrotic disorders include hepaticcirrhosis and mesangial proliferative cell disorders. Hepatic cirrhosisis characterized by the increase in extracellular matrix constituentsresulting in the formation of a hepatic scar. Hepatic cirrhosis cancause diseases such as cirrhosis of the liver. An increasedextracellular matrix resulting in a hepatic scar can also be caused byviral infection such as hepatitis. Lipocytes appear to play a major rolein hepatic cirrhosis.

Mesangial disorders are brought about by abnormal proliferation ofmesangial cells. Mesangial hyperproliferative cell disorders includevarious human renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic micro-angiopathysyndromes, transplant rejection, and glomerulopathies.

Another disease with a proliferative component is rheumatoid arthritis.Rheumatoid arthritis is generally considered an autoimmune disease thatis thought to be associated with activity of autoreactive T cells, andto be caused by autoantibodies produced against collagen and IgE.

Other disorders that can include an abnormal cellular proliferativecomponent include Bechet's syndrome, acute respiratory distress syndrome(ARDS), ischemic heart disease, post-dialysis syndrome, leukemia,acquired immune deficiency syndrome, vasculitis, lipid histiocytosis,septic shock and inflammation in general.

Cutaneous contact hypersensitivity and asthma are just two examples ofimmune responses that can be associated with significant morbidity.Others include atopic dermatitis, eczema, Sjogren's Syndrome, includingkeratoconjunctivitis sicca secondary to Sjogren's Syndrome, alopeciaareata, allergic responses due to arthropod bite reactions, Crohn'sdisease, aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis,ulcerative colitis, cutaneous lupus erythematosus, scleroderma,vaginitis, proctitis, and drug eruptions. These conditions may result inany one or more of the following symptoms or signs: itching, swelling,redness, blisters, crusting, ulceration, pain, scaling, cracking, hairloss, scarring, or oozing of fluid involving the skin, eye, or mucosalmembranes.

In atopic dermatitis, and eczema in general, immunologically mediatedleukocyte infiltration (particularly infiltration of mononuclear cells,lymphocytes, neutrophils, and eosinophils) into the skin importantlycontributes to the pathogenesis of these diseases. Chronic eczema alsois associated with significant hyperproliferation of the epidermis.Immunologically mediated leukocyte infiltration also occurs at sitesother than the skin, such as in the airways in asthma and in the tearproducing gland of the eye in keratoconjunctivitis sicca.

In one non-limiting embodiment compounds of the present invention areused as topical agents in treating contact dermatitis, atopicdermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome,including keratoconjunctivitis sicca secondary to Sjogren's Syndrome,alopecia areata, allergic responses due to arthropod bite reactions,Crohn's disease, aphthous ulcer, iritis, conjunctivitis,keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma,cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, anddrug eruptions. The novel method may also be useful in reducing theinfiltration of skin by malignant leukocytes in diseases such as mycosisfungoides. These compounds can also be used to treat anaqueous-deficient dry eye state (such as immune mediatedkeratoconjunctivitis) in a patient suffering therefrom, by administeringthe compound topically to the eye.

Disease states of conditions which may be treated using compoundsaccording to the present invention include, for example, asthma,autoimmune diseases such as multiple sclerosis, various cancers,ciliopathies, cleft palate, diabetes, heart disease, hypertension,inflammatory bowel disease, mental retardation, mood disorder, obesity,refractive error, infertility, Angelman syndrome, Canavan disease,Coeliac disease, Charcot-Marie-Tooth disease, Cystic fibrosis, Duchennemuscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter'ssyndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease1 (PKD1) or 2 (PKD2) Prader-Willi syndrome, Sickle-cell disease,Tay-Sachs disease, Turner syndrome.

Further disease states or conditions which may be treated by compoundsaccording to the present invention include Alzheimer's disease,Amyotrophic lateral sclerosis (Lou Gehrig's disease), Anorexia nervosa,Anxiety disorder, Atherosclerosis, Attention deficit hyperactivitydisorder, Autism, Bipolar disorder, Chronic fatigue syndrome, Chronicobstructive pulmonary disease, Crohn's disease, Coronary heart disease,Dementia, Depression, Diabetes mellitus type 1, Diabetes mellitus type2, Epilepsy, Guillain-Barré syndrome, Irritable bowel syndrome, Lupus,Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity,Obsessive-compulsive disorder, Panic disorder, Parkinson's disease,Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Stroke,Thromboangiitis obliterans, Tourette syndrome, Vasculitis.

Still additional disease states or conditions which can be treated bycompounds according to the present invention include aceruloplasminemia,Achondrogenesis type II, achondroplasia, Acrocephaly, Gaucher diseasetype 2, acute intermittent porphyria, Canavan disease, AdenomatousPolyposis Coli, ALA dehydratase deficiency, adenylosuccinate lyasedeficiency, Adrenogenital syndrome, Adrenoleukodystrophy, ALA-Dporphyria, ALA dehydratase deficiency, Alkaptonuria, Alexander disease,Alkaptonuric ochronosis, alpha 1-antitrypsin deficiency, alpha-1proteinase inhibitor, emphysema, amyotrophic lateral sclerosis Alströmsyndrome, Alexander disease, Amelogenesis imperfecta, ALA dehydratasedeficiency, Anderson-Fabry disease, androgen insensitivity syndrome,Anemia Angiokeratoma Corporis Diffusum, Angiomatosis retinae (vonHippel-Lindau disease) Apert syndrome, Arachnodactyly (Marfan syndrome),Stickler syndrome, Arthrochalasis multiplex congenital (Ehlers-Danlossyndrome#arthrochalasia type) ataxia telangiectasia, Rett syndrome,primary pulmonary hypertension, Sandhoff disease, neurofibromatosis typeII, Beare-Stevenson cutis gyrata syndrome, Mediterranean fever,familial, Benjamin syndrome, beta-thalassemia, Bilateral AcousticNeurofibromatosis (neurofibromatosis type II), factor V Leidenthrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloomsyndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome(Turner syndrome), Bourneville disease (tuberous sclerosis), priondisease, Birt-Hogg-Dube syndrome, Brittle bone disease (osteogenesisimperfecta), Broad Thumb-Hallux syndrome (Rubinstein-Taybi syndrome),Bronze Diabetes/Bronzed Cirrhosis (hemochromatosis), Bulbospinalmuscular atrophy (Kennedy's disease), Burger-Grutz syndrome (lipoproteinlipase deficiency), CGD Chronic granulomatous disorder, Campomelicdysplasia, biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cridu chat, CAVD (congenital absence of the vas deferens), Caylorcardiofacial syndrome (CBAVD), CEP (congenital erythropoieticporphyria), cystic fibrosis, congenital hypothyroidism, Chondrodystrophysyndrome (achondroplasia), otospondylomegaepiphyseal dysplasia,Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome,Thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome,(familial adenomatous polyposis), Congenital erythropoietic porphyria,Congenital heart disease, Methemoglobinemia/Congenitalmethaemoglobinaemia, achondroplasia, X-linked sideroblastic anemia,Connective tissue disease, Conotruncal anomaly face syndrome, Cooley'sAnemia (beta-thalassemia), Copper storage disease (Wilson's disease),Copper transport disease (Menkes disease), hereditary coproporphyria,Cowden syndrome, Craniofacial dysarthrosis (Crouzon syndrome),Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowdensyndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy),Beare-Stevenson cutis gyrata syndrome, primary hyperoxaluria,spondyloepimetaphyseal dysplasia (Strudwick type), muscular dystrophy,Duchenne and Becker types (DBMD), Usher syndrome, Degenerative nervediseases including de Grouchy syndrome and Dejerine-Sottas syndrome,developmental disabilities, distal spinal muscular atrophy, type V,androgen insensitivity syndrome, Diffuse Globoid Body Sclerosis (Krabbedisease), Di George's syndrome, Dihydrotestosterone receptor deficiency,androgen insensitivity syndrome, Down syndrome, Dwarfism, erythropoieticprotoporphyria Erythroid 5-aminolevulinate synthetase deficiency,Erythropoietic porphyria, erythropoietic protoporphyria, erythropoieticuroporphyria, Friedreich's ataxia-familial paroxysmal polyserositis,porphyria cutanea tarda, familial pressure sensitive neuropathy, primarypulmonary hypertension (PPH), Fibrocystic disease of the pancreas,fragile X syndrome, galactosemia, genetic brain disorders, Giant cellhepatitis (Neonatal hemochromatosis), Gronblad-Strandberg syndrome(pseudoxanthoma elasticum), Gunther disease (congenital erythropoieticporphyria), haemochromatosis, Hallgren syndrome, sickle cell anemia,hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease(von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilfordprogeria syndrome (progeria), Hyperandrogenism, Hypochondroplasia,Hypochromic anemia, Immune system disorders, including X-linked severecombined immunodeficiency, Insley-Astley syndrome, Jackson-Weisssyndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weisssyndrome, Kidney diseases, including hyperoxaluria, Klinefelter'ssyndrome, Kniest dysplasia, Lacunar dementia, Langer-Saldinoachondrogenesis, ataxia telangiectasia, Lynch syndrome,Lysyl-hydroxylase deficiency, Machado-Joseph disease, Metabolicdisorders, including Kniest dysplasia, Marfan syndrome, Movementdisorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome,Multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeneychondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffersyndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, Polycystickidney disease, polyostotic fibrous dysplasia (McCune-Albrightsyndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome,hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome),primary pulmonary hypertension, primary senile degenerative dementia,prion disease, progeria (Hutchinson Gilford Progeria Syndrome),progressive chorea, chronic hereditary (Huntington) (Huntington'sdisease), progressive muscular atrophy, spinal muscular atrophy,propionic acidemia, protoporphyria, proximal myotonic dystrophy,pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb(retinoblastoma), Recklinghausen disease (neurofibromatosis type I),Recurrent polyserositis, Retinal disorders, Retinoblastoma, Rettsyndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levysyndrome, severe achondroplasia with developmental delay and acanthosisnigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia, andadrenal gland (SBLA) syndrome, sclerosis tuberose (tuberous sclerosis),SDAT, SED congenital (spondyloepiphyseal dysplasia congenita), SEDStrudwick (spondyloepimetaphyseal dysplasia, Strudwick type), SEDc(spondyloepiphyseal dysplasia congenita) SEMD, Strudwick type(spondyloepimetaphyseal dysplasia, Strudwick type), Shprintzen syndrome,Skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South-Africangenetic porphyria (variegate porphyria), infantile-onset ascendinghereditary spastic paralysis, Speech and communication disorders,sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Sticklersyndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterindeficiency, beta-thalassemia, Thyroid disease, Tomaculous neuropathy(hereditary neuropathy with liability to pressure palsies), TreacherCollins syndrome, Triplo X syndrome (triple X syndrome), Trisomy 21(Down syndrome), Trisomy X, VHL syndrome (von Hippel-Lindau disease),Vision impairment and blindness (Alström syndrome), Vrolik disease,Waardenburg syndrome, Warburg Sjo Fledelius Syndrome,Weissenbacher-Zweymuller syndrome, Wolf-Hirschhorn syndrome, WolffPeriodic disease, Weissenbacher-Zweymuller syndrome and Xerodermapigmentosum, among others.

The term “neoplasia” or “cancer” is used throughout the specification torefer to the pathological process that results in the formation andgrowth of a cancerous or malignant neoplasm, i.e., abnormal tissue thatgrows by cellular proliferation, often more rapidly than normal andcontinues to grow after the stimuli that initiated the new growth cease.Malignant neoplasms show partial or complete lack of structuralorganization and functional coordination with the normal tissue and mostinvade surrounding tissues, metastasize to several sites, and are likelyto recur after attempted removal and to cause the death of the patientunless adequately treated. As used herein, the term neoplasia is used todescribe all cancerous disease states and embraces or encompasses thepathological process associated with malignant hematogenous, ascitic andsolid tumors. Exemplary cancers which may be treated by the presentcompounds either alone or in combination with at least one additionalanti-cancer agent include squamous-cell carcinoma, basal cell carcinoma,adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas,cancer of the bladder, bowel, breast, cervix, colon, esophagus, head,kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach;leukemias; benign and malignant lymphomas, particularly Burkitt'slymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas;myeloproliferative diseases; sarcomas, including Ewing's sarcoma,hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheralneuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using compounds according to the present invention include, forexample, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineagelymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cellLeukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, BurkittsLymphoma, B-cell ALL, Philadelphia chromosome positive ALL andPhiladelphia chromosome positive CML.

Additional cancers which may be treated using the disclosed compoundsaccording to the present invention include, for example, acutegranulocytic leukemia, acute lymphocytic leukemia (ALL), acutemyelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenalcancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma,angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Celllymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrowcancer, bowel cancer, brain cancer, brain stem glioma, breast cancer,triple (estrogen, progesterone and HER-2) negative breast cancer, doublenegative breast cancer (two of estrogen, progesterone and HER-2 arenegative), single negative (one of estrogen, progesterone and HER-2 isnegative), estrogen-receptor positive, HER2-negative breast cancer,estrogen receptor-negative breast cancer, estrogen receptor positivebreast cancer, metastatic breast cancer, luminal A breast cancer,luminal B breast cancer, Her2-negative breast cancer, HER2-positive ornegative breast cancer, progesterone receptor-negative breast cancer,progesterone receptor-positive breast cancer, recurrent breast cancer,carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma,chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma,cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ(DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophagealcancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer,fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer,gastrointestinal cancer, gastrointestinal carcinoid cancer,gastrointestinal stromal tumors (GIST), germ cell tumor glioblastomamultiforme (GBM), glioma, hairy cell leukemia, head and neck cancer,hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer,infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma(MC), inflammatory breast cancer (IBC), intestinal Cancer, intrahepaticbile duct cancer, invasive/infiltrating breast cancer, Islet cellcancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer,leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer,liposarcoma, liver cancer, lobular carcinoma in situ, low-gradeastrocytoma, lung cancer, lymph node cancer, lymphoma, male breastcancer, medullary carcinoma, medulloblastoma, melanoma, meningioma,Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous,mesothelioma metastatic breast cancer, metastatic melanoma metastaticsquamous neck cancer, mixed gliomas, monodermal teratoma, mouth cancermucinous carcinoma, mucosal melanoma, multiple myeloma, MycosisFungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngealcancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs),non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cellcancer, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer,oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma,osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germcell tumor, ovarian primary peritoneal carcinoma, ovarian sex cordstromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma,paranasal sinus cancer, parathyroid cancer, pelvic cancer, penilecancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer,pheochromocytoma, pilocytic astrocytoma, pineal region tumor,pineoblastoma, pituitary gland cancer, primary central nervous system(CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma,renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, softtissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, smallcell lung cancer (SCLC), small intestine cancer, spinal cancer, spinalcolumn cancer, spinal cord cancer, squamous cell carcinoma, stomachcancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throatcancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsilcancer, transitional cell cancer, tubal cancer, tubular carcinoma,undiagnosed cancer, ureteral cancer, urethral cancer, uterineadenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvarcancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-celllineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, AdultT-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma,Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL,Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia(JMML), acute promyelocytic leukemia (a subtype of AML), large granularlymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large Bcell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissuelymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large Bcell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenicmarginal zone lymphoma (SMZL); intravascular large B-cell lymphoma;primary effusion lymphoma; or lymphomatoid granulomatosis;; B-cellprolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable,splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacyticlymphoma; heavy chain diseases, for example, Alpha heavy chain disease,Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma,solitary plasmacytoma of bone; extraosseous plasmacytoma; primarycutaneous follicle center lymphoma, T cell/histocyte rich large B-celllymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus(EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-celllymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma,plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associatedmulticentric, Castleman disease; B-cell lymphoma, unclassifiable, withfeatures intermediate between diffuse large B-cell lymphoma, or B-celllymphoma, unclassifiable, with features intermediate between diffuselarge B-cell lymphoma and classical Hodgkin lymphoma.

In one embodiment the cancer is NUT midline carcinioma.

In one embodiment the cancer is adenoid cystic carcinoma.

The term “bioactive agent” is used to describe an agent, other than acompound according to the present invention, which is used incombination with the present compounds as an agent with biologicalactivity to assist in effecting an intended therapy, inhibition and/orprevention/prophylaxis for which the present compounds are used.Preferred bioactive agents for use herein include those agents whichhave pharmacological activity similar to that for which the presentcompounds are used or administered and include for example, anti-canceragents, antiviral agents, especially including anti-HIV agents andanti-HCV agents, antimicrobial agents, antifungal agents, etc.

In one embodiment, a method is provided for treating multiple myelomacomprising administering to a patient an effective amount of a compounddescribed herein, or a pharmaceutically acceptable salt, isotopicanalog, or prodrug thereof, optionally in a pharmaceutically acceptablecarrier to form a composition. In another embodiment, a compounddescribed herein or a pharmaceutically acceptable salt, isotopic analog,or prodrug thereof, optionally in a pharmaceutically acceptable carrierto form a composition, for use in a method of treating multiple myeloma,wherein the method comprises administering the compound to a patient.

In one embodiment, a method is provided for managing the progression ofmultiple myeloma comprising administering to a patient an effectiveamount of a compound described herein, or a pharmaceutically acceptablesalt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition. In anotherembodiment, a compound described herein, or a pharmaceuticallyacceptable salt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition, for use in amethod of managing the progression of multiple myeloma, wherein themethod comprises administering the compound to a patient.

In one embodiment, a method is provided for inducing a therapeuticresponse as assessed by the International Uniform Response Criteria(IURC) for Multiple Myeloma (described in Durie B. G. M; et al.“International uniform response criteria for multiple myeloma. Leukemia2006, 10(10):1-7) in a patient having multiple myeloma comprisingadministering to the patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition.

In another embodiment, a method is provided to achieve a stringentcomplete response, complete response, or very good partial response, asassessed by the IURC for Multiple Myeloma in a patient having multiplemyeloma comprising administering to the patient an effective amount of acompound described herein, or a pharmaceutically acceptable salt,isotopic analog, or prodrug thereof, optionally in a pharmaceuticallyacceptable carrier to form a composition.

In another embodiment, a method is provided to achieve an increase inoverall survival, progression-free survival, event-free survival, timeto process, or disease-free survival in a patient having multiplemyeloma comprising administering to the patient an effective amount of acompound described herein, or a pharmaceutically acceptable salt,isotopic analog, or prodrug thereof, optionally in a pharmaceuticallyacceptable carrier to form a composition.

In another embodiment, a method is provided to achieve an increase inoverall survival in a patient having multiple myeloma comprisingadministering to the patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition.

In another embodiment, a method is provided to achieve an increase inprogression-free survival in a patient having multiple myelomacomprising administering to the patient an effective amount of acompound described herein, or a pharmaceutically acceptable salt,isotopic analog, or prodrug thereof, optionally in a pharmaceuticallyacceptable carrier to form a composition.

In another embodiment, a method is provided to achieve an increase inevent-free survival in a patient having multiple myeloma comprisingadministering to the patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition.

In another embodiment, a method is provided to achieve an increase intime to progression in a patient having multiple myeloma comprisingadministering to the patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition.

In another embodiment, a method is provided to achieve an increase indisease-free survival in a patient having multiple myeloma comprisingadministering to the patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition.

Methods are also provided to treat patients who have been previouslytreated for multiple myeloma but are non-responsive to standardtherapies in addition to those who have not been previously treated.Additional methods are provided to treat patients who have undergonesurgery in an attempt to treat multiple myeloma in addition to those whohave not undergone surgery. Methods are also provided to treat patientswho have previously undergone transplant therapy in addition to thosewho have not.

The compounds described herein may be used in the treatment ormanagement of multiple myeloma that is relapsed, refractory, orresistant. In some embodiments, the multiple myeloma is primary,secondary, tertiary, quadruply or quintuply relapsed. In one embodiment,the compounds described herein may be used to reduce, maintain, oreliminate minimal residual disease (MRD).

The types of multiple myeloma that may be treated with the compoundsdescribed herein include, but are not limited to: monoclonal gammopathyof undetermined significance (MGUS); low risk, intermediate risk, orhigh risk multiple myeloma; newly diagnosed multiple myeloma, includinglow risk, intermediate risk, or high risk newly diagnosed multiplemyeloma); transplant eligible and transplant ineligible multiplemyeloma; smoldering (indolent) multiple myeloma (including low risk,intermediate risk, or high risk smoldering multiple myeloma); activemultiple myeloma; solitary plasmocytoma; plasma cell leukemia; centralnervous system multiple myeloma; light chain myeloma; non-secretorymyeloma; Immunoglobulin D myeloma; and Immunoglobulin E myeloma.

In some embodiments, the compounds described herein may be used in thetreatment or management of multiple myeloma characterized by geneticabnormalities, for example but not limited to: Cyclin D translocations(for example, t(11;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32); ort(6;20);); MMSET translocations (for example t(4;14)(p16;q32); MAFtranslocations (for example t(14;16)(q32;a32); t(20;22);t(16;22)(q11;q13); or t(14;20)(q32;q11); or other chromosome factors(for example deletion of 17p13 or chromosome 13; del(17/17p),nonhyperdiploidy, and gain (1q)).

In one embodiment, a method is provided for treating or managingmultiple myeloma comprising administering to a patient an effectiveamount of a compound described herein, or a pharmaceutically acceptablesalt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition, as inductiontherapy.

In one embodiment, a method is provided for treating or managingmultiple myeloma comprising administering to a patient an effectiveamount of a compound described herein, or a pharmaceutically acceptablesalt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition, asconsolidation therapy.

In one embodiment, a method is provided for treating or managingmultiple myeloma comprising administering to a patient an effectiveamount of a compound described herein, or a pharmaceutically acceptablesalt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition, asmaintenance therapy.

In one embodiment, the multiple myeloma is plasma cell leukemia.

In one embodiment, the multiple myeloma is high risk multiple myeloma.In some embodiments, the high risk multiple myeloma is relapsed orrefractory. In one embodiment, the high risk multiple myeloma hasrelapsed within 12 months of the first treatment. In another embodiment,the high risk multiple myeloma is characterized by geneticabnormalities, for example, one or more of del(17/17p) andt(14;16)(q32;q32). In some embodiments, the high risk multiple myelomais relapsed or refractory to one, two or three previous treatments.

In one embodiment, the multiple myeloma has a p53 mutation. In oneembodiment, the p53 mutation is a Q331 mutation. In one embodiment, thep53 mutation is a R273H mutation. In one embodiment, the p53 mutation isa K132 mutation. In one embodiment, the p53 mutation is a K132Nmutation. In one embodiment, the p53 mutation is a R337 mutation. In oneembodiment, the p53 mutation is a R337L mutation. In one embodiment, thep53 mutation is a W146 mutation. In one embodiment, the p53 mutation isa S261 mutation. In one embodiment, the p53 mutation is a S261Tmutation. In one embodiment, the p53 mutation is a E286 mutation. In oneembodiment, the p53 mutation is a E286K mutation. In one embodiment, thep53 mutation is a R175 mutation.

In one embodiment, the p53 mutation is a R175H mutation. In oneembodiment, the p53 mutation is a E258 mutation. In one embodiment, thep53 mutation is a E258K mutation. In one embodiment, the p53 mutation isa A161 mutation. In one embodiment, the p53 mutation is a A161Tmutation.

In one embodiment, the multiple myeloma has a homozygous deletion ofp53. In one embodiment, the multiple myeloma has a homozygous deletionof wild-type p53. In one embodiment, the multiple myeloma has wild-typep53.

In one embodiment, the multiple myeloma shows activation of one or moreoncogenic drivers. In one embodiment, the one or more oncogenic driversare selected from the group consisting of C-MAF, MAFB, FGFR3, MMset,Cyclin D1, and Cyclin D. In one embodiment, the multiple myeloma showsactivation of C-MAF. In one embodiment, the multiple myeloma showsactivation of MAFB. In one embodiment, the multiple myeloma showsactivation of FGFR3 and MMset. In one embodiment, the multiple myelomashows activation of C-MAF, FGFR3, and MMset. In one embodiment, themultiple myeloma shows activation of Cyclin D1. In one embodiment, themultiple myeloma shows activation of MAFB and Cyclin D1. In oneembodiment, the multiple myeloma shows activation of Cyclin D.

In one embodiment, the multiple myeloma has one or more chromosomaltranslocations. In one embodiment, the chromosomal translocation ist(14;16). In one embodiment, the chromosomal translocation is t(14;20).In one embodiment, the chromosomal translocation is t(4; 14). In oneembodiment, the chromosomal translocations are t(4;14) and t(14;16). Inone embodiment, the chromosomal translocation is t(11;14). In oneembodiment, the chromosomal translocation is t(6;20). In one embodiment,the chromosomal translocation is t(20;22). In one embodiment, thechromosomal translocations are t(6;20) and t(20;22). In one embodiment,the chromosomal translocation is t(16;22). In one embodiment, thechromosomal translocations are t(14;16) and t(16;22). In one embodiment,the chromosomal translocations are t(14;20) and t(11;14).

In one embodiment, the multiple myeloma has a Q331 p53 mutation,activation of C-MAF, and a chromosomal translocation at t(14; 16). Inone embodiment, the multiple myeloma has homozygous deletion of p53,activation of C-MAF, and a chromosomal translocation at t(14; 16). Inone embodiment, the multiple myeloma has a K132N p53 mutation,activation of MAFB, and a chromosomal translocation at t(14;20). In oneembodiment, the multiple myeloma has wild type p53, activation of FGFR3and MMset, and a chromosomal translocation at t(4; 14). In oneembodiment, the multiple myeloma has wild type p53, activation of C-MAF,and a chromosomal translocation at t(14;16). In one embodiment, themultiple myeloma has homozygous deletion of p53, activation of FGFR3,MMset, and C-MAF, and chromosomal translocations at t(4;14) andt(14;16). In one embodiment, the multiple myeloma has homozygousdeletion of p53, activation of Cyclin D1, and a chromosomaltranslocation at t(11;14). In one embodiment, the multiple myeloma has aR337L p53 mutation, activation of Cyclin D1, and a chromosomaltranslocation at t(11;14). In one embodiment, the multiple myeloma has aW146 p53 mutation, activation of FGFR3 and MMset, and a chromosomaltranslocation at t(4; 14). In one embodiment, the multiple myeloma has aS261T p53 mutation, activation of MAFB, and chromosomal translocationsat t(6;20) and t(20;22). In one embodiment, the multiple myeloma has aE286K p53 mutation, by activation of FGFR3 and MMset, and a chromosomaltranslocation at t(4; 14). In one embodiment, the multiple myeloma has aR175H p53 mutation, activation of FGFR3 and MMset, and a chromosomaltranslocation at t(4; 14). In one embodiment, the multiple myeloma has aE258K p53 mutation, activation of C-MAF, and chromosomal translocationsat t(14;16) and t(16;22). In one embodiment, the multiple myeloma haswild type p53, activation of MAFB and Cyclin D1, and chromosomaltranslocations at t(14;20) and t(11;14). In one embodiment, the multiplemyeloma has a A161T p53 mutation, activation of Cyclin D, and achromosomal translocation at t(11;14).

In some embodiments, the multiple myeloma is transplant eligible newlydiagnosed multiple myeloma. In other embodiments, the multiple myelomais transplant ineligible newly diagnosed multiple myeloma.

In some embodiments, the multiple myeloma shows early progression (forexample less than 12 months) following initial treatment. In otherembodiments, the multiple myeloma shows early progression (for exampleless than 12 months) following autologous stem cell transplant. Inanother embodiment, the multiple myeloma is refractory to lenalidomide.In another embodiment, the multiple myeloma is refractory topomalidomide. In some such embodiments, the multiple myeloma ispredicted to be refractory to pomalidomide (for example, by molecularcharacterization). In another embodiment, the multiple myeloma isrelapsed or refractory to 3 or more treatments and was exposed to aproteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib,oprozomib, or marizomib) and an immunomodulatory compound (for examplethalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide), ordouble refractory to a proteasome inhibitor and an immunomodulatorycompound. In still other embodiments, the multiple myeloma is relapsedor refractory to 3 or more prior therapies, including for example, aCD38 monoclonal antibody (CD38 mAb, for example, daratumumab orisatuximab), a proteasome inhibitor (for example, bortezomib,carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound(for example thalidomide, lenalidomide, pomalidomide, iberdomide, oravadomide) or double refractory to a proteasome inhibitor orimmunomodulatory compound and a CD38 mAb. In still other embodiments,the multiple myeloma is triple refractory, for example, the multiplemyeloma is refractory to a proteasome inhibitor (for example,bortezomib, carfilzomib, ixazomib, oprozomib or marizomib), animmunomodulatory compound (for example thalidomide, lenalidomide,pomalidomide, iberdomide, or avadomide), and one other active agent, asdescribed herein.

In one embodiment, a method is provided for treating or managingrelapsed or refractory multiple myeloma in patients with impaired renalfunction or a symptom thereof comprising administering to a patient aneffective amount of a compound described herein, or a pharmaceuticallyacceptable salt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition.

In another embodiment, a method is provided for treatingor managingrelapsed or refractory multiple myeloma in frail patients comprisingadministering to a patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition, wherein the frail patient is characterized byineligibility for induction therapy or intolerance to dexamethasonetreatment. In other embodiments, the frail patient is elderly, forexample, older than 65 years old.

In another embodiment, a method is provided for treating or managingfourth line relapsed or refractory multiple myeloma comprisingadministering to a patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition.

In another embodiment, a method is provided for treating or managingnewly diagnosed, transplant-ineligible multiple myeloma comprisingadministering to a patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition.

In another embodiment, a method is provided for treating or managingnewly diagnosed, transplant-ineligible multiple myeloma comprisingadministering to a patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition, as maintenance therapy after another therapy ortransplant.

In another embodiment, a method is provided for treating or managinghigh risk multiple myeloma that is relapsed or refractory to one, two,or three previous treatments comprising administering to a patient aneffective amount of a compound described herein, or a pharmaceuticallyacceptable salt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition.

In some embodiments, the patient to be treated by one of the compoundsdescribed herein has not be treated with multiple myeloma therapy priorto administration. In some embodiments, the patient to be treated by oneof the compounds described herein has been treated by multiple myelomatherapy prior to administration. In some embodiments, the patient to betreated by one of the compounds described herein has developed drugresistant to the multiple myeloma therapy.

In some embodiments, the patient to be treated by one of the compoundsdescribed herein has developed resistance to one, two, or three multiplemyeloma therapies, wherein the therapies are selected from a CD38antibody (CD38 mAB, for example, daratumumab or isatuximab), aproteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib, ormarizomib), and an immunomodulatory compound (for example thalidomide,lenalidomide, pomalidomide, iberdomide, or avodomide).

The compounds described herein can be used to treat a patient regardlessof patient's age. In some embodiments, the subject is 18 years or older.In other embodiments, the subject is more than 18, 25, 35, 40, 45, 50,55, 60, 65, or 70 years old. In other embodiments, the patient is lessthan 65 years old. In other embodiments, the patient is more than 65years old. In one embodiment, the patient is an elderly multiple myelomapatient, such as a patient older than 65 years old. In one embodiment,the patient is an elderly multiple myeloma patient, such as a patientolder than 75 years old.

V. Combination Therapy

The compounds of Formula Ia, Formula Ib, Formula II, Formula IIIa,Formula IIIb, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,Formula XIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-tcan be used in an effective amount alone or in combination to treat ahost such as a human with a disorder as described herein.

The disclosed compounds described herein can be used in an effectiveamount alone or in combination with another compound of the presentinvention or another bioactive agent to treat a host such as a humanwith a disorder as described herein.

The term “bioactive agent” is used to describe an agent, other than theselected compound according to the present invention, which can be usedin combination or alternation with a compound of the present inventionto achieve a desired result of therapy. In one embodiment, the compoundof the present invention and the bioactive agent are administered in amanner that they are active in vivo during overlapping time periods, forexample, have time-period overlapping Cmax, Tmax, AUC or otherpharmacokinetic parameter. In another embodiment, the compound of thepresent invention and the bioactive agent are administered to a host inneed thereof that do not have overlapping pharmacokinetic parameter,however, one has a therapeutic impact on the therapeutic efficacy of theother.

In one aspect of this embodiment, the bioactive agent is an immunemodulator, including but not limited to a checkpoint inhibitor,including as non-limiting examples, a PD-1 inhibitor, PD-L1 inhibitor,PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor,V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, smallmolecule, peptide, nucleotide, or other inhibitor. In certain aspects,the immune modulator is an antibody, such as a monoclonal antibody.

VI. Pharmaceutical Compositions

The compounds of Formula Ia, Formula Ib, Formula II, Formula IIIa,Formula IIIb, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,Formula XIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-tas disclosed herein can be administered as the neat chemical, but aremore typically administered as a pharmaceutical composition, thatincludes an effective amount for a host, typically a human, in need ofsuch treatment for any of the disorders described herein. Accordingly,the disclosure provides pharmaceutical compositions comprising aneffective amount of compound or pharmaceutically acceptable salttogether with at least one pharmaceutically acceptable carrier for anyof the uses described herein. The pharmaceutical composition may containa compound or salt as the only active agent, or, in an alternativeembodiment, the compound and at least one additional active agent.

In certain embodiments the pharmaceutical composition is in a dosageform that contains from about 0.1 mg to about 2000 mg, from about 10 mgto about 1000 mg, from about 100 mg to about 800 mg, or from about 200mg to about 600 mg of the active compound and optionally from about 0.1mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100mg to about 800 mg, or from about 200 mg to about 600 mg of anadditional active agent in a unit dosage form. Examples are dosage formswith at least 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600,700, or 750 mg of active compound, or its salt. The pharmaceuticalcomposition may also include a molar ratio of the active compound and anadditional active agent. For example the pharmaceutical composition maycontain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1 orfrom about 1.5:1 to about 4:1 of an anti-inflammatory orimmunosuppressing agent. Compounds disclosed herein may be administeredorally, topically, parenterally, by inhalation or spray, sublingually,via implant, including ocular implant, transdermally, via buccaladministration, rectally, as an ophthalmic solution, injection,including ocular injection, intraveneous, intra-aortal, intracranial,subdermal, intraperitioneal, subcutaneous, transnasal, sublingual, orrectal or by other means, in dosage unit formulations containingconventional pharmaceutically acceptable carriers. For ocular delivery,the compound can be administered, as desired, for example, viaintravitreal, intrastromal, intracameral, sub-tenon, sub-retinal,retro-bulbar, peribulbar, suprachorodial, conjunctival, subconjunctival,episcleral, periocular, transcleral, retrobulbar, posteriorjuxtascleral, circumcorneal, or tear duct injections, or through amucus, mucin, or a mucosal barrier, in an immediate or controlledrelease fashion or via an ocular device.

The pharmaceutical composition may be formulated as any pharmaceuticallyuseful form, e.g., as an aerosol, a cream, a gel, a pill, an injectionor infusion solution, a capsule, a tablet, a syrup, a transdermal patch,a subcutaneous patch, a dry powder, an inhalation formulation, in amedical device, suppository, buccal, or sublingual formulation,parenteral formulation, or an ophthalmic solution. Some dosage forms,such as tablets and capsules, are subdivided into suitably sized unitdoses containing appropriate quantities of the active components, e.g.,an effective amount to achieve the desired purpose.

Carriers include excipients and diluents and must be of sufficientlyhigh purity and sufficiently low toxicity to render them suitable foradministration to the patient being treated. The carrier can be inert orit can possess pharmaceutical benefits of its own. The amount of carrieremployed in conjunction with the compound is sufficient to provide apractical quantity of material for administration per unit dose of thecompound.

Classes of carriers include, but are not limited to binders, bufferingagents, coloring agents, diluents, di sintegrants, emulsifiers,flavorants, glidents, lubricants, preservatives, stabilizers,surfactants, tableting agents, and wetting agents. Some carriers may belisted in more than one class, for example vegetable oil may be used asa lubricant in some formulations and a diluent in others. Exemplarypharmaceutically acceptable carriers include sugars, starches,celluloses, powdered tragacanth, malt, gelatin; talc, and vegetableoils. Optional active agents may be included in a pharmaceuticalcomposition, which do not substantially interfere with the activity ofthe compound of the present invention.

The pharmaceutical compositions/combinations can be formulated for oraladministration. These compositions can contain any amount of activecompound that achieves the desired result, for example between 0.1 and99 weight % (wt. %) of the compound and usually at least about 5 wt. %of the compound. Some embodiments contain from about 25 wt. % to about50 wt. % or from about 5 wt. % to about 75 wt. % of the compound.

Formulations suitable for rectal administration are typically presentedas unit dose suppositories. These may be prepared by admixing the activecompound with one or more conventional solid carriers, for example,cocoa butter, and then shaping the resulting mixture.

Formulations suitable for topical application to the skin preferablytake the form of an ointment, cream, lotion, paste, gel, spray, aerosol,or oil. Carriers which may be used include petroleum jelly, lanoline,polyethylene glycols, alcohols, transdermal enhancers, and combinationsof two or more thereof.

Formulations suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Formulationssuitable for transdermal administration may also be delivered byiontophoresis (see, for example, Pharmaceutical Research 3 (6):318(1986)) and typically take the form of an optionally buffered aqueoussolution of the active compound. In one embodiment, microneedle patchesor devices are provided for delivery of drugs across or into biologicaltissue, particularly the skin. The microneedle patches or devices permitdrug delivery at clinically relevant rates across or into skin or othertissue barriers, with minimal or no damage, pain, or irritation to thetissue.

Formulations suitable for administration to the lungs can be deliveredby a wide range of passive breath driven and active power drivensingle/-multiple dose dry powder inhalers (DPI). The devices mostcommonly used for respiratory delivery include nebulizers, metered-doseinhalers, and dry powder inhalers. Several types of nebulizers areavailable, including jet nebulizers, ultrasonic nebulizers, andvibrating mesh nebulizers. Selection of a suitable lung delivery devicedepends on parameters, such as nature of the drug and its formulation,the site of action, and pathophysiology of the lung.

The compounds described herein and the pharmaceutically acceptable saltscan be used as therapeutically active substances, e.g. in the form ofpharmaceutical preparations. The pharmaceutical preparations can beadministered orally, e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatin capsules, solutions, emulsions orsuspensions. The administration can, however, also be effected rectally,e.g. in the form of suppositories, or parenterally, e.g. in the form ofinjection solutions.

The compounds described herein and the pharmaceutically acceptable saltsthereof can be processed with pharmaceutically inert, inorganic ororganic carriers for the production of pharmaceutical preparations.Lactose, corn starch or derivatives thereof, talc, stearic acids or itssalts and the like can be used, for example, as such carriers fortablets, coated tablets, dragées and hard gelatin capsules. Suitablecarriers for soft gelatin capsules are, for example, vegetable oils,waxes, fats, semi-solid and liquid polyols and the like. Depending onthe nature of the active substance no carriers are however usuallyrequired in the case of soft gelatin capsules. Suitable carriers for theproduction of solutions and syrups are, for example, water, polyols,glycerol, vegetable oil and the like. Suitable carriers forsuppositories are, for example, natural or hardened oils, waxes, fats,semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain pharmaceuticallyacceptable auxiliary substances such as preservatives, solubilizers,stabilizers, wetting agents, emulsifiers, sweeteners, colorants,flavorants, salts for varying the osmotic pressure, buffers, maskingagents or antioxidants. They can also contain still othertherapeutically valuable substances.

Medicaments containing a compound of the present invention or apharmaceutically acceptable salt thereof and a therapeutically inertcarrier are also provided by the present invention, as is a process fortheir production, which comprises bringing one or more compounds ofFormula I and/or pharmaceutically acceptable salts thereof and, ifdesired, one or more other therapeutically valuable substances into agalenical administration form together with one or more therapeuticallyinert carriers.

The dosage can vary within wide limits and will, of course, have to beadjusted to the individual requirements in each particular case. In thecase of oral administration the dosage for adults can vary from about0.01 mg to about 1000 mg per day of a compound of general Formula VII,Formula XIII, or of the corresponding amount of a pharmaceuticallyacceptable salt thereof. The daily dosage may be administered as singledose or in divided doses and, in addition, the upper limit can also beexceeded when this is found to be indicated.

The following examples illustrate the present invention without limitingit, but serve merely as representative thereof. The pharmaceuticalpreparations conveniently contain about 1-500 mg, particularly 1-100 mg,of a compound of Formula XIV. Examples of compositions according to theinvention are:

EXAMPLE A

Tablets of the following composition are manufactured in the usualmanner:

TABLE 1 possible tablet composition mg/tablet ingredient 5 25 100 500Compound of Formula VII or XIII 5 25 100 500 Lactose Anhydrous DTG 125105 30 150 Sta-Rx 1500 6 6 6 60 Microcrystalline Cellulose 30 30 30 450Magnesium Stearate 1 1 1 1 Total 167 167 167 831

Manufacturing Procedure

-   1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.-   2. Dry the granules at 50° C.-   3. Pass the granules through suitable milling equipment.-   4. Add ingredient 5 and mix for three minutes; compress on a    suitable press.

EXAMPLE B-1

Capsules of the following composition are manufactured:

TABLE 2 possible capsule ingredient composition mg/capsule ingredient 525 100 500 Compound of Formula VII or XIII 5 25 100 500 Hydrous Lactose159 123 148 — Corn Starch 25 35 40 70 Talk 10 15 10 25 MagnesiumStearate 1 2 2 5 Total 200 200 300 600

Manufacturing Procedure

-   1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.-   2. Add ingredients 4 and 5 and mix for 3 minutes.-   3. Fill into a suitable capsule.

The compound of Formula VII or XIII, lactose and corn starch are firstlymixed in a mixer and then in a comminuting machine. The mixture isreturned to the mixer; the talc is added thereto and mixed thoroughly.The mixture is filled by machine into suitable capsules, e.g. hardgelatin capsules.

EXAMPLE B-2

Soft Gelatin Capsules of the following composition are manufactured:

TABLE 3 possible soft gelatin capsule ingredient composition ingredientmg/capsule Compound of Formula VII or XIII 5 Yellow wax 8 HydrogenatedSoya bean oil 8 Partially hydrogenated plant oils 34 Soya bean oil 110Total 165

TABLE 4 possible soft gelatin capsule composition ingredient mg/capsuleGelatin 75 Glycerol 85% 32 Karion 83 8 (dry matter) Titan dioxide 0.4Iron oxide yellow 1.1 Total 116.5

Manufacturing Procedure

The compound of Formula VII or XIII is dissolved in a warm melting ofthe other ingredients and the mixture is filled into soft gelatincapsules of appropriate size. The filled soft gelatin capsules aretreated according to the usual procedures.

EXAMPLE C

Suppositories of the following composition are manufactured:

TABLE 5 possible suppository composition ingredient mg/supp. Compound ofFormula VII or XIII 15 Suppository mass 1285 Total 1300

Manufacturing Procedure

The suppository mass is melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C. Thereupon, the finely powdered compoundof Formula VII or XIII is added thereto and stirred until it hasdispersed completely. The mixture is poured into suppository molds ofsuitable size, left to cool; the suppositories are then removed from themolds and packed individually in wax paper or metal foil.

EXAMPLE D

Injection solutions of the following composition are manufactured:

TABLE 6 possible injection solution composition ingredient mg/injectionsolution. Compound of Formula VII or XIII 3 Polyethylene Glycol 400 150acetic acid q.s. ad pH 5.0 water for injection solutions ad 1.0 ml

Manufacturing Procedure

The compound of Formula VII or XIII is dissolved in a mixture ofPolyethylene Glycol 400 and water for injection (part). The pH isadjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml byaddition of the residual amount of water. The solution is filtered,filled into vials using an appropriate overage and sterilized.

EXAMPLE E

Sachets of the following composition are manufactured:

TABLE 7 possible sachet composition ingredient mg/sachet Compound ofFormula VII or XIII 50 Lactose, fine powder 1015 Microcrystallinecellulose (AVICEL PH 102) 1400 Sodium carboxymethyl cellulose 14Polyvinylpyrrolidon K 30 10 Magnesium stearate 10 Flavoring additives 1Total 2500

Manufacturing Procedure

The compound of Formula VII or XIII is mixed with lactose,microcrystalline cellulose and sodium carboxymethyl cellulose andgranulated with a mixture of polyvinylpyrrolidone in water. Thegranulate is mixed with magnesium stearate and the flavoring additivesand filled into sachets.

VII. Use of Compounds

The compounds of Formula Ia, Formula Ib, Formula II, Formula IIIa,Formula IIIb, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,Formula XIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-tof the present invention bind to the ubiquitously expressed E3 ligaseprotein cereblon (CRBN) and alter the substrate specificity of the CRBNE3 ubiquitin ligase complex, resulting in breakdown of intrinsicdownstream proteins. The present compounds are thus useful for thetreatment or prophylaxis of various cancers.

In one aspect, the present invention provides compounds Formula Ia,Formula Ib, Formula II, Formula IIIa, Formula IIIb, Formula IV, FormulaV, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, FormulaXI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XIV-a toXIV-x, or Formula XV-a to XV-t as described herein for use astherapeutically active substance.

In a further aspect, the present invention provides compounds of FormulaIa, Formula Ib, Formula II, Formula IIIa, Formula IIIb, Formula IV,Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X,Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, FormulaXIV-a to XIV-x, or Formula XV-a to XV-t as defined herein, for use inthe treatment or prophylaxis of cancer.

In a further aspect, the present invention provides the use of acompound of Formula Ia, Formula Ib, Formula II, Formula IIIa, FormulaIIIb, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII,Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, FormulaXIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-t asdefined herein for the treatment or prophylaxis of cancer.

In a further aspect, the present invention provides a method of treatingor preventing cancer, comprising administering a therapeuticallyeffective amount of a compound of Formula Ia, Formula Ib, Formula II,Formula IIIa, Formula IIIb, Formula IV, Formula V, Formula VI, FormulaVII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII,Formula XIII, Formula XIV, Formula XV, Formula XIV-a to XIV-x, orFormula XV-a to XV-t as defined herein to a subject.

In a further aspect, the present invention provides the use of acompound of Formula Ia, Formula Ib, Formula II, Formula IIIa, FormulaIIIb, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII,Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, FormulaXIV, Formula XV Formula XIV-a to XIV-x, or Formula XV-a to XV-t asdefined herein for the manufacture of a medicament for the treatment orprophylaxis of cancer.

The compounds of Formula Ia, Formula Ib, Formula II, Formula IIIa,Formula IIIb, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,Formula XIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-tmay also be used to prepare bifunctional degrader compounds by linkingthem to a protein-targeting moiety that binds to a target protein or toa target polypeptide, in analogy to the bifunctional compounds whichhave been described e.g. in WO2013020557, WO2013063560, WO 2013106643,WO2015160845, WO2016011906, WO2016105518, WO2017007612, WO2017024318,and WO2017117473.

GENERAL SYNTHETIC EXAMPLES

The preparation of compounds of the present invention may be carried outin sequential or convergent synthetic routes. Syntheses of the compoundsof the invention are shown in the following schemes in the descriptionof the specific examples. The skills required for carrying out thereactions and purification of the resulting products are known to thoseskilled in the art. The substituents and indices used in the followingdescription of the processes have the significance given herein beforeunless indicated to the contrary.

In more detail, the compounds of the invention can be manufactured bythe methods given below, by the methods given in the examples or byanalogous methods. Appropriate reaction conditions for the individualreaction steps are known to a person skilled in the art. The reactionsequence is not limited to the one displayed in the schemes below,however, depending on the starting materials and their respectivereactivity the sequence of reaction steps can be freely altered.Starting materials are either commercially available or can be preparedby methods analogous to the methods given below, by methods described inreferences cited in the description or in the examples, or by methodsknown in the art.

-   Step A: Formation of the glutarimide ring of 3 can be accomplished    by reaction between (2-amino-2-oxo-ethyl)-phosphonium salt 1 (CAS    25361-54-0) and ethyl acrylate 2 in the presence of an aqueous base    such as lithium hydroxide, sodium hydroxide or potasium hydroxide in    protic organic solvents such as methanol or ethanol. Preferred    conditions are NaOH in methanol at room temperature for 16 hours.-   Step B: Conjugated olefin 4 can be prepared by Wittig-Horner-Emmons    reaction of phosphanylidene 3 with paraformaldehyde. The reaction is    carried out at elevated temperatures in halogenated solvents such as    dichloromethane or 1,2-dichloroethane. Preferred conditions are    dichloroethane at 80° C. for 30 minutes.-   Step C: Formation of the pyrrolidine ring of 6 can be accomplished    by a 1,3-cycloaddition reaction between dipolarophile 4 and an    azomethine ylide which is generated in situ from precursor    N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methanamine 5    (CAS 93102-05-7) by treatment with an acid catalyst such as    trifluoracetic acid or triflic acid, according to the method of    Terao et al. Chem. Pharm. Bull. 1985, 33, 2762. The reaction is    carried out in halogenated solvents such as dichloromethane or    1,2-dichloroethane. Preferred conditions are trifluoracetic acid in    dichloromethane at room temperature for 16 hours.-   Step D: Removal of the benzyl protecting group of 6 to afford    secondary amine 7 can be accomplished by a two-step procedure    according to the method of Olofson et al. J. Org. Chem. 1984,    49, 2081. The first step involves treatment of tertiary amine 6 with    1-chloroethyl chloroformate (CAS 50893-53-3). The reaction is    carried out in halogenated solvents such as dichloromethane or    1,2-dichloroethane at elevated temperature. In a second step, the    carbamate compound resulting from the first step is thermally    decomposed by heating in an alcoholic solvent such as methanol or    ethanol at elevated temperature. Preferred conditions are    dichloromethane at 80° C. for 12 hours for the first step, and    methanol at 65° C. for 2 hours for the second step.

-   Step A: Nitrile ester 10 can be prepared by conjugate addition of    the enolate of nitrile ester 8 (CAS 6283-71-2) tounsaturated ester 9    (CAS 1663-39-4). The enolate of 8 can be pre-formed in situ by    treatment of 8 with a tertiary amine base such as triethylamine or    N,N-diisopropylethylamine prior to addition of unsaturated ester 9    to the reaction mixture. Preferred conditions for enolisation are    triethylamine in a mixture of methanol and water at 0-5° C. for 30    minutes. Preferred conditions for the conjugate addition are 0-5° C.    for 90 minutes followed by warming to room temperature for 2 hours.-   Step B: Lactam 11 can be prepared by selective reduction of the    nitrile group of nitrile ester 10 to afford the corresponding    primary amine which can then be cyclised in situ to afford    lactam 11. The selective reduction of the nitrile group in the    presence of the ester groups can be accomplished by catalytic    hydrogenation. Preferred conditions are treatment with Raney nickel    as hydrogenation catalyst under a hydrogen atmosphere at elevated    pressure, preferably at a pressure of 40 atm, in methanol at room    temperature for 16 hours.-   Step C: Transesterification of mixed methyl/tent-butyl ester 11 to    all methyl ester 12 can be accomplished by reaction with methanol in    the presence of an acid catalyst such as hydrochloric acid,    sulphuric acid or p-toluenesulphonic acid. The reaction is    preferably carried out using neat methanol as solvent. Preferred    conditions are hydrochloric acid in methanol at 60° C. for 2 hours.-   Step D: Conversion of di-ester 12 to di-amide 13 can be accomplished    by reaction with 4-methoxybenzylamine at elevated temperature and    pressure. The reaction is preferably carried out using neat    methoxybenzylamine as solvent. Preferred conditions are stirring the    reaction mixture at 200° C. in a sealed vessel under microwave    irradiation for 2 hours.-   Step E: Formation of the glutarimide ring of 14 can be accomplished    by cyclisation of di-amide 13 in the presence of an acid such as    p-toluenesulphonic acid in an aromatic solvent such as benzene,    toluene or xylene at elevated temperature. Preferred conditions are    p-toluenesulphonic acid in xylene at 145° C. for 2 hours.-   Step F: N-alkylation of lactam 14 can be accomplished by treatment    with an alkyl halide, such as an alkyl bromide or an alkyl iodide,    in the presence of a base such as sodium hydride or potassium    hydride in an aprotic organic solvent such as tetrahydrofuran,    dioxane, toluene or N,N-dimethylformamide at elevated temperature.    In the case where the alkyl halide reagent is methyl iodide,    preferred conditions are sodium hydride in toluene at 60° C. for 1    hour.-   Step G: Removal of the 4-methoxybenzyl protecting group of 15 to    afford glutarimide 16 can be accomplished by treatment with an    oxidising agent such as ammonium cerium(IV) nitrate in a mixture of    water and a miscible polar organic solvent such as acetonitrile or    dioxane. Preferred conditions are ammonium cerium(IV) nitrate in    aqueous acetonitrile at room temperature for 1 hour.

The substituents are as described herein and in the claims.

-   Step A: Amide bond formation can be accomplished by a coupling    reaction between a carboxylic acid 17 and pyrrolidine-glutarimide 7    in the presence of a coupling reagent such as DCC, EDC, TBTU or HATU    in the presence of an organic base such as triethylamine,    N,N-diisopropylethylamine or N-methylmorpholine in halogenated    solvents such as dichloromethane or 1,2-dichloroethane or ethereal    solvents such as diethyl ether, dioxane, THF, DME or TBME or polar    non-protic organic solvent such as N,N-dimethylformamide at room    temperature or at elevated temperatures for 2-18 hours. Preferred    conditions are HATU with N,N-diisopropylethylamine in    N,N-dimethylformamide at room temperature for 3 hours.

The substituents are as described in the claims, EWG is anelectron-withdrawing group such as —CN, —CO₂R, —SO₂R or —NO₂ and hal isF or Cl.

-   Step A: Nucleophilic aromatic substitution (S_(N)Ar) reaction can be    accomplished by reaction of pyrrolidine-glutarimide 7 with an    electron-deficient mono- or fused bicylic heteroaromatic compound 19    bearing a suitable leaving group such as fluorine or chlorine, in    the presence of an organic base such as triethylamine,    N,N-diisopropylethylamine or N-methylmorpholine in polar non-protic    organic solvent such as N,N-dimethylformamide or N-methylpyrrolidone    at elevated temperature.

Examples of suitable electron-deficient heteroaromatic compounds 19bearing a suitable leaving group include, but are not limited to, methyl6-chloronicotinate (CAS 73781-91-6), 2-chlorothiazolo[4,5-b]pyridine(CAS 152170-30-4), 1-fluoro-4-nitrobenzene (CAS 350-46-9),2-chloro-5-nitro-1H-benzo[d]imidazole (CAS 5955-72-6),2-chlorobenzo[d]thiazole (CAS 615-20-3), methyl2-chloro-1H-benzo[d]imidazole-7-carboxylate (CAS 1171129-05-7), methyl2-chloropyrimidine-4-carboxylate (CAS 149849-94-5), 2-chloroquinoline(CAS 612-62-4), 2-chlorobenzo[d]thiazol-6-amine (CAS 2406-90-8),2-chlorooxazolo[4,5-b] pyridine (CAS 325976-45-2),2-chloro-1-methyl-1H-benzo[d]imidazole (CAS 1849-02-1),2-chlorothiazolo[4,5-c]pyridine (CAS 884860-63-3), methyl2-chlorobenzo[d]thiazole-6-carboxylate (CAS 90792-69-1), methyl2-chlorothiazole-4-carboxylate (CAS 850429-61-7), methyl2-chlorothiazole-5-carboxylate (CAS 72605-86-8), tent-butyl6-chloronicotinate (CAS 115309-57-4), 2-chloro-5-nitropyridine (CAS4548-45-2), or methyl 6-chloro-2-picolinic acid methyl ester (CAS6636-55-1). Preferred conditions are N,N-diisopropylethylamine inN,N-dimethylformamide at 110° C. for 24 hours.

As an illustrative example, degrader compounds targeting the BETbromodomain BRD4 can be prepared based on the known BRD4 ligand JQ1(Filippakopoulos, P. et al. Nature 2010, 468, 1067-1073, CAS1268524-70-4). The synthesis employs the corresponding carboxylic acidderivative 25 (CAS 202592-23-2).

-   Step A: Amide bond formation can be accomplished by a coupling    reaction between amine 7 and a linker-containing compound 21 bearing    a terminal carboxylic acid functionality and a terminal    BOC-protected amine functionality. The reaction is carried out in    the presence of a coupling reagent such as DCC, EDC, TBTU or HATU in    the presence of an organic base such as triethylamine,    N,N-diisopropylethylamine, N-methylmorpholine or    4-(N,N-dimethylamino)pyridine in halogenated solvents such as    dichloromethane or 1,2-dichloroethane or ethereal solvents such as    diethyl ether, dioxane, THF, DME or TBME or polar non-protic organic    solvent such as N,N-dimethylformamide at room temperature or at    elevated temperatures for 2-18 hours. Preferred conditions are HATU    with N,N-diisopropylethylamine in N,N-dimethylformamide at room    temperature for 18 hours.

Alternatively, amide bond formation can be accomplished by a couplingreaction between amine 7 and an acyl chloride compound 22 which has beenperformed in situ from a linker-containing compound 21 bearing aterminal carboxylic acid functionality and a terminal BOC-protectedamine functionality. The acyl chloride compound 22 can be prepared insitu from the corresponding carboxylic acid 21 by treatment with1-chloro-N,N,2-trimethylpropenylamine (CAS 26189-59-3) in halogenatedsolvents such as dichloromethane or 1,2-dichloroethane at a temperaturebetween 0° C. and room temperature, according to the method of Ghosezand co-workers (J. Chem. Soc., Chem. Commun. 1979, 1180; Org. Synth.1980, 59, 26-34). Amide bond formation can then be accomplished byreaction of the acyl chloride compound 22 with amine 7 in halogenatedsolvents such as dichloromethane or 1,2-dichloroethane. Preferredconditions are dichoromethane at room temperature for 2 hours.

Step B: Removal of the Boc N-protecting group of 23 can be effected withmineral acids such as HCl, H₂SO₄ or H₃PO₄ or organic acids such asCF₃COOH, CHCl₂COOH, HOAc or p-toluenesulfonic acid in solvents such asCH₂Cl₂, CHCl₃, THF, EtOAc, Dioxane, MeOH, EtOH or H₂O at 0° C. to refluxtemperature. Preferred conditions are 4 M aq. HCl in dioxane and ethylacetate at room temperature for 1 hour.

-   Step C: Amide bond formation can be accomplished by a coupling    reaction between carboxylic acid 25 and amine 24 in the presence of    a coupling reagent such as DCC, EDC, TBTU or HATU in the presence of    an organic base such as triethylamine, N,N-diisopropylethylamine or    N-methylmorpholine in halogenated solvents such as dichloromethane    or 1,2-dichloroethane or ethereal solvents such as diethyl ether,    dioxane, THF, DME or TBME or polar non-protic organic solvent such    as N,N-dimethylformamide at room temperature or at elevated    temperatures for 2-18 hours. Preferred conditions are HATU with    N,N-diisopropylethylamine in N,N-dimethylformamide at room    temperature for 3 hours.

The substituents X are as described in the claims and A is NH or CH₂

Step A: Amide bond formation can be accomplished by a coupling reactionbetween a spiro-piperidine 28 and a carboxylic acid 29 in the presenceof a coupling reagent such as DCC, EDC, TBTU or HATU in the presence ofan organic base such as triethylamine, N,N-diisopropylethylamine orN-methylmorpholine in halogenated solvents such as dichloromethane or1,2-dichloroethane or ethereal solvents such as diethyl ether, dioxane,THF, DME or TBME or polar non-protic organic solvent such asN,N-dimethylformamide at room temperature or at elevated temperaturesfor 2-18 hours.

Preferred conditions are HATU with N,N-diisopropylethylamine inN,N-dimethylformamide at room temperature for 15 hours.

Examples of suitable spiro-piperidine compounds 28 include, but are notlimited to, 1,3,8-triazaspiro[4.5]decane-2,4-dione (CAS 13625-39-3) or2, 8-diazaspiro[4 5]decane-1,3-dione (CAS 2079-25-6), or theircorresponding salts 1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride(CAS 13625-48-4) or 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride(CAS 2696-03-9). Alternatively, amide bond formation can be accomplishedby a coupling reaction between a spiro-piperidine 28 and an acylchloride compound 29a which has been preformed in situ from a carboxylicacid 29. The acyl chloride compound 29a can be prepared in situ from thecorresponding carboxylic acid 29 by treatment with 1-chloro-N,N,2-trimethylpropenylamine (CAS 26189-59-3) in halogenated solvents suchas dichloromethane or 1,2-dichloroethane, or in ethereal solvents suchas diethyl ether, dioxane, THF, DME or TBME, at a temperature between 0°C. and room temperature, according to the method of Ghosez andco-workers (J. Chem. Soc., Chem. Commun. 1979, 1180; Org. Synth. 1980,59, 26-34). Amide bond formation can then be accomplished by reaction ofthe acyl chloride compound 29a with spiro-piperidine 28 in the presenceof an organic base such as triethylamine, N,N-diisopropylethylamine orN-methylmorpholine in halogenated solvents such as dichloromethane or1,2-dichloroethane, or in ethereal solvents such as diethyl ether,dioxane, THF, DME or TBME. Preferred conditions areN,N-diisopropylethylamine in THF at room temperature for 2 hours.

The substituents are as described in the claims, A is NH or CH₂, EWG isan electron-withdrawing group such as —CN, —CO₂R, —SO₂R or —NO₂ and halis F or Cl.

Step A: Nucleophilic aromatic substitution (SNAr) reaction can beaccomplished by reaction of a spiro-piperidine 28 with anelectron-deficient mono- or fused bicylic heteroaromatic compound 31bearing a suitable leaving group such as fluorine or chlorine, in thepresence of an organic base such as triethylamine,N,N-diisopropylethylamine or N-methylmorpholine in polar non-proticorganic solvent such as N,N-dimethylformamide or N-methylpyrrolidone atelevated temperature.

Examples of suitable spiro-piperidine compounds 28 include, but are notlimited to, 1,3,8-triazaspiro[4. 5]decane-2,4-dione (CAS 13625-39-3) or2, 8-diazaspiro[4. 5]decane-1,3-dione (CAS 2079-25-6), or theircorresponding salts 1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride(CAS 13625-48-4) or 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride(CAS 2696-03-9).

Examples of suitable electron-deficient heteroaromatic compounds 21bearing a suitable leaving group include, but are not limited to,2-chlorobenzo[d]thiazole (CAS 615-20-3), 2-chlorothiazolo[4,5-b]pyridine (CAS 152170-30-4), methyl 6-chloronicotinate (CAS73781-91-6), 2-chloro-5-nitropyridine (CAS 4548-45-2), or1-fluoro-4-nitrobenzene (CAS 350-46-9). Preferred conditions areN,N-diisopropylethylamine in N,N-dimethylformamide at 120° C. for 2hours.

REPRESENTATIVE EXAMPLES OF THE PRESENT INVENTION

The following examples are provided for illustration of the invention.They should not be considered as limiting the scope of the invention,but merely as being representative thereof.

Isolation and purification of the compounds and intermediates describedherein can be effected, if desired, by any suitable separation orpurification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography,thick-layer chromatography, preparative low or high-pressure liquidchromatography or a combination of these procedures. Specificillustrations of suitable separation and isolation procedures can be hadby reference to the preparations and examples herein below. However,other equivalent separation or isolation procedures could, of course,also be used. Racemic mixtures of chiral compounds of formula I can beseparated using chiral HPLC. Racemic mixtures of chiral syntheticintermediates may also be separated using chiral HPLC.

EXAMPLE 1 2,7-Diazaspiro[4.5]decane-6,8-dione

a) 3-(Triphenyl-λ⁵-phosphanyhdene)piperidine-2,6-dione

To a solution of (2-amino-2-oxo-ethyl)-triphenyl-phosphonium chloride(CAS 25361-54-0, 70.0 g, 219 mmol, 1.00 eq, and NaOH (8.04 g, 201 mmol,0.92 eq) in methanol (300 mL) was added ethyl acrylate (20.7 g, 240mmol, 21.6 mL, 1.10 eq). The reaction mixture was stirred at 25° C. for16 hours. The starting material was consumed and the product wasdetected by LC/MS. The reaction mixture was filtered, washed withmethanol (2×20 mL) and petrol ether (100mL), and dried to afford3-(triphenyl-λ⁵-phosphanylidene)piperidine-2,6-dione (35.0 g, crude) asa white solid that was used directly for the next step without furtherpurification. MS (ISP): 374.1 ([M+H]⁺).

b) 3-Methylenepiperidine-2,6-dione

A solution of 3-(triphenyl-λ⁵-phosphanylidene)piperidine-2,6-dione (35.0g, 93.7 mmol, 1.00 eq) and paraformaldehyde (10.1 g, 112 mmol, 1.20 eq)in dichloroethane (200 mL) was stirred at 80° C. for 30 minutes. Thestarting material was consumed and the product was detected by LC/MS.The reaction was filtered and concentrated in vacuo. The residue waspurified by preparative HPLC to afford 3-methylenepiperidine-2,6-dione(4.30 g, 34.4 mmol, 36.7% yield) as an off-white solid. MS (ISP): 126.0([M+H]⁺).

c) 2-Benzyl-2,7-diazaspiro[4.5]decane-6,8-dione

To a solution of 3-methylenepiperidine-2,6-dione (4.30 g, 34.36 mmol,1.00 eq) andN-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methanamine (CAS93102-05-7, 8.97 g, 37.8 mmol, 1.10 eq) in dichloromethane (200 mL) wasadded trifluoracetic acid (2.55 g, 22.3 mmol, 1.65 mL, 0.65 eq). Thereaction was stirred at 25° C. for 16 hours. The starting material wasconsumed and the product was detected by LC/MS. The reaction wasquenched with saturated NaHCO₃ (200 mL), extracted with dichloromethane(50 mL), washed with brine (100 mL), dried with Na₂SO₄, filtered andconcentrated in vacuo. The solid residue obtained was triturated with amixture of ethyl acetate and petrol ether (1:10) and purified bypreparative HPLC to afford 2-benzyl-2,7-diazaspiro[4.5]decane-6,8-dione(3.00 g, 11.6 mmol, 33.8% yield) as a white solid. MS (ISP): 259.1([M+H]⁺).

d) 2,7-Diazaspiro[4.5]decane-6,8-dione

To a solution of 2-benzyl-2,7-diazaspiro[4.5]decane-6,8-dione (1.50 g,5.81 mmol, 1.00 eq) in dichloroethane (50.0 mL) was added 1-chloroethylchloroformate (CAS 50893-53-3, 1.66 g, 11.6 mmol, 2.00 eq). The reactionmixture was stirred at 80° C. for 12 hours. The solution wasconcentrated in vacuo, the residue was dissolved in methanol (50.0 mL)and stirred at 65° C. for 2 hours. After concentration in vacuo, ¹H NMRshowed the presence of starting material. The residue was dissolved indichloroethane (100 ml) and treated again with 1-chloroethylchloroformate (1.66 g, 11.6 mmol, 4.00 eq) at 80° C. for 12 hours. Afterevaporation of the solvent, methanol was added and the solution wasstirred at 65° C. for 2 hours. The solvent was evaporated and theresidue was dissolved in dichloromethane, stirred for 5 hours andfiltered to afford 2,7-diazaspiro[4.5]decane-6,8-dione as itshydrochloride salt (300 mg, 1.78 mmol, 30.7% yield) as a grey solid. MS(ISP): 169.1 ([M+H]⁺).

EXAMPLE 2 2-Methyl-2,7-diazaspiro[4.5]decane-3,6,8-trione

a) 4-O-tert-Butyl 1-0,2-O-dimethyl 2-cyanobutane-1,2,4-tricarboxylate

To a solution of dimethyl 2-cyanobutanedioate (CAS 6283-71-2, 10.0 g,58.4 mmol, 1.00 eq) in methanol (60.0 mL) and water (60.0 mL) was addedtriethylamine (8.87 g, 87.6 mmol, 12.1 mL, 1.50 eq) at 0- 5° C. Afterstirring for 30 minutes, tent-butyl prop-2-enoate (CAS 1663-39-4, 8.99g, 70.1 mmol, 10.2 mL, 1.20 eq) was added to the reaction mixture. Themixture was stirred at 0-5° C. for 1.5 hours and was allowed to warm to25° C. and stirred for a further 2 hours. TLC showed that startingmaterial was consumed and one new spot was detected. The reactionmixture was acidified with 2 N aq HCl to pH=4 and extracted with EtOAc(3×50 mL). The combined organic layers were washed with brine (50 mL),dried over Na₂SO₄, filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by chromatography (SiO₂,petrol ether: ethyl acetate=20:1 to 4:1) to afford 4-O-tert-butyl1-O,2-O-dimethyl 2-cyanobutane-1,2,4-tricarboxylate (10.0 g, 33.4 mmol,57.2%) as a yellow gum. ¹H NMR: 400 MHz, CDCl₃: δ3.82-3.87 (m, 3H), 3.73(s, 3H), 3.09 (d, J=17.07 Hz, 1H), 2.83 (d, J=17.32 Hz, 1H), 2.47- 2.61(m, 1H), 2.31- 2.43 (m, 1H), 2.10- 2.25 (m, 2H), 2.03 (s, 1H), 1.43 (s,9H).

b) Methyl 3-(3-tert-butoxy-3-oxo-propyl)-5-oxo-pyrrolidine-3-carboxylate

4-O-tert-butyl 1-O,2-O-dimethyl 2-cyanobutane-1,2,4-tricarboxylate (5.00g, 16.7 mmol, 1.00 eq) was dissolved in methanol (200 mL) and Raney-Ni(143 mg, 1.67 mmol, 0.10 eq) was added to the mixture. The reactionmixture was hydrogenated with H₂ (40 psi) for 16 hours. According toLC/MS, the starting material was consumed and the desired compound wasdetected. The solution was decanted with a pipette and the catalyst waswashed with methanol. The filtrate was concentrated under reducedpressure to afford methyl3-(3-tert-butoxy-3-oxo-propyl)-5-oxo-pyrrolidine-3-carboxylate (4.00 g,14.7 mmol, 88.3%) as a yellow solid that was used directly for the nextreaction. MS (ISP): 543.2 ([2M+H]⁺).

c) Methyl 3-(3-methoxy-3-oxo-propyl)-5-oxo-pyrrolidine-3-carboxylate

To a solution of methyl3-(3-tert-butoxy-3-oxo-propyl)-5-oxo-pyrrolidine-3-carboxylate (2.00 g,7.37 mmol, 1.00 eq) in methanol (25.0 mL) was added concentrated HCl(0.8 ml) while stirring. The mixture was heated at 60° C. for 2 hours.LC/MS showed the starting material was consumed and the desired compoundwas detected. The reaction mixture was quenched by the addition ofsaturated NaHCO₃ (50 mL) and extracted with ethyl acetate (3×50 ml). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered, and the filtrate was concentrated under reducedpressure to afford crude methyl3-(3-methoxy-3-oxo-propyl)-5-oxo-pyrrolidine-3-carboxylate (1.60 g) as ayellow gum, which was used directly for the next reaction withoutfurther purification. MS (ISP): 459.2 ([2M+H]⁺).

d)N-[(4-Methoxyphenyl)methyl]-3-[3-[(4-methoxyphenyl)methylamino]-3-oxo-propyl]-5-oxo-pyrrolidine-3-carboxamide

A mixture of methyl3-(3-methoxy-3-oxo-propyl)-5-oxo-pyrrolidine-3-carboxylate (800 mg, 3.49mmol, 1.00 eq) and 4-methoxybenzylamine (CAS 2393-23-9, 15.0 g, 109mmol, 14.2 mL, 31.3 eq.) were heated together at 200° C. for 2 hoursunder microwave irradiation. LC/MS showed the starting material wasconsumed and the desired compound was detected. The reaction mixture wasdiluted with water (100 mL), acidified to pH=7 with 1 N aqueous HCl, andextracted with dichloromethane (3×200 mL). The combined organic layerswere washed with brine (100 mL), dried over Na₂SO₄, filtered, and thefiltrate was evaporated in vacuo. The residue was purified bypreparative HPLC to afford N-[(4-methoxyphenyl)methyl]-3-[3-[(4-methoxyphenyl)methylamino]-3-oxo-propyl]-5-oxo-pyrrolidine-3-carboxamide(1.00 g, 2.28 mmol, 32.7%) as a yellow gum. MS (ISP): 440.1([M+H]⁺).

e) 7-[(4-Methoxyphenyl)methyl]-2,7-diazaspiro[4.5]decane-3,6,8-trione

To a solution ofN-[(4-methoxyphenyl)methyl]-3-[3-[(4-methoxyphenyl)methylamino]-3-oxo-propyl]-5-oxo-pyrrolidine-3-carboxamide(1.00 g, 2.28 mmol, 1.00 eq) in xylene (20.0 mL) was added p-toluenesulfonic acid monohydrate (500 mg, 2.63 mmol, 1.15 eq). The reactionmixture was degassed and purged with nitrogen three times and was thenstirred at 145° C. for 2 hours under N₂ atmosphere. LC/MS showed thestarting material was consumed and the desired compound was detected.The reaction mixture was diluted with water (50 mL) and extracted withdichloromethane (3×50 mL). The combined organic layers were washed withbrine (50 mL), dried over Na₂SO₄, filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by flashsilica gel chromatography to afford7-[(4-methoxyphenyl)methyl]-2,7-diazaspiro[4.5]decane-3,6,8-trione (200mg, 662 μmol, 29%) as a yellow gum. MS (ISP): 303 .2([M+H]⁺).

f) 7-[(4-Methoxyphenyl)methyl]-2-methyl-2,7-diazaspiro [4.5]decane-3,6,8-trione

To a solution of7-[(4-methoxyphenyl)methyl]-2,7-diazaspiro[4.5]decane-3,6,8-trione (200mg, 662 μmol, 1.00 eq) in toluene (20.0 mL) was added sodium hydride(66.0 mg, 1.65 mmol, 60% purity, 2.49 eq) followed by methyl iodide (235mg, 1.66 mmol, 2.50 eq).The reaction mixture was stirred at 60° C. for 1hour under N₂ atmosphere. LC/MS showed the starting material wasconsumed and the desired compound was detected. The reaction mixture wasquenched by addition of a saturated solution of aqueous NH₄Cl (50 mL)and extracted with dichloromethane (3×50 mL). The combined organiclayers were washed with brine (50 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude material was purified by flash columnchromatography (silica gel, eluent: 0 to 5% of methanol indichloromethane) to afford 7-[(4-methoxyphenyl)methyl]-2-methyl-2,7-diazaspiro[4.5]decane-3,6,8-trione (100 mg, 316μmol, 47.8%) as a yellow gum. MS (ISP): 317.1([M+H]⁺).

g) 2-Methyl-2,7-diazaspiro [4.5]decane-3,6,8-trione

A solution of7-[(4-methoxyphenyl)methyl]-2-methyl-2,7-diazaspiro[4.5]decane-3,6,8-trione(300 mg, 948 μmol, 1.00 eq) in acetonitrile (10.0 mL) was treated withammonium cerium (IV) nitrate (1.04 g, 1.90 mmol, 2.00 eq) in H₂O (5.00mL). The mixture was stirred at 25° C. for 1 hour. LC/MS showed thestarting material was consumed and the desired compound was detected.The reaction mixture was diluted with water (20 ml) and set to pH=7 byadding a saturated solution of aqueous NaHCO₃. The solid was filtered,concentrated under reduced pressure, dissolved in anhydrous methanol (20ml) and filtered. The filtrate was concentrated in vacuo. The crude waspurified by prep-HPLC to afford2-methyl-2,7-diazaspiro[4.5]decane-3,6,8-trione (35.0 mg, 178 μmol,18.8%) as a white solid. MS (ISP): 197.1([M+H]⁺).

EXAMPLE 3 (2-(2-Phenylacetyl)-2,7-diazaspiro [4.5]decane-6,8-dione

a) 2-(2-(4-Bromophenyl)acetyl)-2,7-diazaspiro[4.5]decane-6,8-dione

To a suspension of 2-(4-bromophenyl) acetic acid (84.4 mg, 392 μmol, eq.1.1) and 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (60 mg, 357μmol, eq. 1) in N,N-dimethylformamide (1.5 ml) were added DIPEA (138 mg,187 1.07 mmol, eq. 3) and HATU (271 mg, 713 μmol, eq. 2) at roomtemperature. The reaction mixture was stirred for 3 hours. The reactionmixture was partitioned between ethyl acetate (40 ml) and 0.5 M aqueoussodium hydroxide solution (20 ml). The layers were separated. Theaqueous layer was extracted with ethyl acetate (2×25 ml). The combinedorganic layers were washed with brine (20 ml), dried over anhydroussodium sulfate and concentrated in vacuo. The product was purified byreversed phase HPLC followed by lyophilisation to afford2-(2-(4-bromophenyl)acetyl)-2,7-diazaspiro[4.5]decane-6,8-dione (44mg,120 μmol, 34%) as an off-white solid. MS (ISP): 366.9 ([M+H]⁺).

b) 2-(2-Phenylacetyl)-2,7-diazaspiro[4.5]decane-6,8-dione

To a stirred suspension of2-(2-(4-bromophenyl)acetyl)-2,7-diazaspiro[4.5]decane-6,8-dione (39 mg,107 μmol, eq. 1) in methanol (5 ml) was added 10% palladium on charcoal(11.4 mg, 10.7 μmol, Eq. 0.1). The reaction mixture was stirred for 4hours at room temperature under an atmosphere of hydrogen. The catalystwas collected by filtration, washing with methanol. The filtrate wasthen concentrated in vacuo. The crude material was purified by flashchromatography (silica gel, eluent: 0 to 10% of methanol indichloromethane) to afford2-(2-phenylacetyl)-2,7-diazaspiro[4.5]decane-6,8-dione (8.5mg, 107 μmol,28%) as an off-white solid. MS (ISP): 287 ([M+H]⁺).

EXAMPLE 42-(2,3-Dihydro-1H-indene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as a white solid in analogy to Example3(a) using 2,3-dihydro-1H-indene-1-carboxylic acid (CAS 14381-42-1) inplace of 2-(4-bromophenyl)acetic acid. MS (ISP): 374.1 ([M+H]⁺).

EXAMPLE 5 2-(3-Nitrobenzoyl)-2,7-diazaspiro[4.5]decane-6,8-dione

To a mixture of 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (200mg, 1.19 mmol, eq. 1) and a solution of HATU in N,N-dimethylformamide0.269 M (4.87 ml, 1.31 mmol, eq. 1.34) was added 3-nitrobenzoic acid(238 mg, 1.43 mmol, eq. 1.2) followed by DIPEA (615 mg, 831 μl, 4.76mmol, eq. 4). The reaction mixture was stirred for 3 hours and stayedovernight at room temperature. The reaction mixture was partitionedbetween ethyl acetate and water. The layers were separated. The aqueousphase was extracted a second time with ethyl acetate. The combinedorganic layer was dried over MgSO₄ and concentrated in vacuo. Theproduct was purified via column chromatography (silica gel, eluent: 0 to10% of methanol in dichloromethane) to afford2-(3-nitrobenzoyl)-2,7-diazaspiro[4.5]decane-6,8-dione as a pink powder(50 mg, 158 μmol, 13.3%). MS (ISP): 318.1 ([M+H]⁺).

EXAMPLE 6 Methyl 6-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)nicotinate

To a stirred solution of 2,7-diazaspiro[4.5]decane-6,8-dionehydrochloride (50 mg, 244 μmol, Eq. 1) in N,N-dimethylformamide (0.6 ml)was added methyl 6-chloronicotinate (CAS 73781-91-6, 41.9 mg, 244 μmol,eq. 1) and DIPEA (94.7 mg, 128 μl, 733 μmol, eq. 3). The reactionmixture was shaken for 24 hours at 110° C. and was directly purified bypreparative HPLC followed by lyophilisation to afford methyl6-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)nicotinate (30.2 mg, 99.6μmol, 40.8% yield) as a white solid. MS (ISP): 304.3([M+H]⁺).

EXAMPLE 72-(Thiazolo[4,5-b]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as a white solid in analogy to Example 6using 2-chlorothiazolo[4,5-b]pyridine (CAS 152170-30-4) in place ofmethyl 6-chloronicotinate. MS (ISP): 304.3 ([M+H]⁺).

EXAMPLE 8 2-(4-Nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as a white solid in analogy to Example 6using 1-fluoro-4-nitrobenzene (CAS 350-46-9) in place of methyl6-chloronicotinate. MS (ISP): 290.3 ([M+H]⁺).

EXAMPLE 92-(5-Nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as a white solid in analogy to Example 6using 2-chloro-5-nitro-1H-benzo[d]imidazole (CAS 5955-72-6) in place ofmethyl 6-chloronicotinate. MS (ISP): 330.3 ([M+H]⁺).

EXAMPLE 10 (+)-2-(4-Nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione(Enantiomer 1)

a) 2-(4-Nitrophenyl)-2,7-diazaspiro [4.5]decane-6,8-dione

The title compound was obtained as a white solid in analogy to Example 6using 1-fluoro-4-nitrobenzene (CAS 350-46-9) in place of methyl6-chloronicotinate. MS (ISP): 330.3 ([M+H]⁺).

b) (+)-2-(4-Nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione (Enantiomer1)

The enantiomers of 2-(4-nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione(415 mg) were separated using chiral HPLC (column: Chiralcel OD, eluent:heptane/ethanol+NH₄OAc (60:40), pressure: 18 bar; flow rate: 35 ml/min)affording (+)-2-(4-nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione (62mg, yellow solid), retention time=19.0 min. MS (ISP): 290.3 ([M+H]⁺).

EXAMPLE 11 (+2-(4-Nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione(Enantiomer 2)

The enantiomers of 2-(4-nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione(415 mg) were separated using chiral HPLC (column: Reprosil Chiral-NR,eluent: heptane/ethanol+NH₄OAc (60:40), pressure: 18 bar; flow rate: 35ml/min) affording(−)-2-(4-nitrophenyl)-2,7-diazaspiro[4.5]decane-6,8-dione (65 mg, yellowsolid), retention time=25.5 min. MS (ISP): 290.3 ([M+H]⁺).

EXAMPLE 12 2-(Benzo [d]thiazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

To a suspension of 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (23mg, 112 μmol, Eq. 1) and DIPEA (43.6 mg, 58.9 337 μmol, Eq. 3) in DMF(0.5 ml) was added 2-chlorobenzo[d]thiazole (CAS 615-20-3, 21 mg, 16.1μl, 124 μmol, eq. 1.1). The reaction mixture was stirred at 100° C. for1 hour. The reaction mixture was poured into a mixture ofethylacetate/tetrahydrofuran (1:1). The organic layer was washed withwater followed by brine, dried over Na₂SO₄ and concentrated in vacuo.The crude material was purified by flash column chromatography (silicagel, eluent: 0 to 5% of methanol in dichloromethane) to afford2-(benzo[d]thiazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (10 mg,33.2 μmol, 29.5%) as a white solid. MS (ISP): 302.1 ([M+H]⁺).

EXAMPLE 13 Methyl2-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)-1H-benzo[d]imidazole-7-carboxylate

To a stirred solution of 2,7-diazaspiro[4.5]decane-6,8-dionehydrochloride (50 mg, 244 μmol, Eq. 1) in N,N-dimethylformamide (600 μl)were added methyl 2-chloro-1H-benzo[d]imidazole-7-carboxylate (CAS1171129-05-7, 51.5 mg, 244 μmol, eq. 1) and DIPEA (94.7 mg, 128 733μmol, eq. 3). The reaction mixture was shaken at 110° C. for 17 hours.The reaction mixture was partitioned between water and a 1:1 mixture ofethyl acetate and THF. The organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated in vacuo. The crude product wastaken in CH₂Cl₂ and stirred at room temperature for 30 minutes. Theproduct was collected by filtration, washed with CH₂Cl₂ and dried toafford methyl2-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)-1H-benzo[d]imidazole-7-carboxylate(19 mg, 55.5 μmol, 22.7% yield) as light brown solid. MS (ISP):343.3([M+H]⁺).

EXAMPLE 14 Methyl2-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)pyrimidine-4-carboxylate

The title compound was obtained as a light brown solid in analogy toExample 13 using methyl 2-chloropyrimidine-4-carboxylate (CAS149849-94-5) in place of methyl2-chloro-1H-benzo[d]imidazole-7-carboxylate. MS (ISP): 305.3 ([M+H]⁺).

EXAMPLE 15 2-(Quinolin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as a light brown solid in analogy toExample 13 using 2-chloroquinoline (CAS 612-62-4) in place of methyl2-chloro-1H-benzo[d]imidazole-7-carboxylate. MS (ISP): 296.3 ([M+H]⁺).

EXAMPLE 162-(6-Aminobenzo[d]thiazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

To a suspension of 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (23mg, 112 μmol, Eq. 1) and 2-chlorobenzo[d]thiazol-6-amine (CAS 2406-90-8,20.8 mg, 112 μmol, eq. 1) in N,N-dimethylformamide (0.5 ml) was addedDIPEA (43.6 mg, 58.9 337 μmol, eq. 3). The reaction mixture was stirredat 100° C. for 1 hour then at 120° C. for 1 hour and finally at 130° C.overnight. The reaction mixture was poured into a mixture ofethylacetate/tetrahydrofuran (1:1), the organic layer was washed withwater followed by brine, dried over Na₂SO₄ and concentrated in vacuo.The crude material was purified by flash column chromatography (silicagel, eluent: 0 to 5% of methanol in dichloromethane) to afford2-(6-aminobenzo[d]thiazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (3mg, 9.48 μmol, 8.44%) as a yellow solid. MS (ISP): 317.1 ([M+H]⁺).

EXAMPLE 172-(Oxazolo[4,5-b]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as awhite solid in analogy to Example 12using 2-chlorooxazolo[4,5-b]pyridine (CAS 325976-45-2) in place of2-chlorobenzo[d]thiazole. MS (ISP): 287.1 ([M+H]⁺).

EXAMPLE 18 2-(Benzo[d]oxazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as a white solid in analogy to Example12 using 2-chlorobenzo[d]oxazole (CAS 615-18-9) in place of2-chlorobenzo[d]thiazole. MS (ISP): 286.1 ([M+H]⁺).

EXAMPLE 192-(1-Methyl-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as a brown solid in analogy to Example12 using 2-chloro-1-methyl-1H-benzo[d]imidazole (CAS 1849-02-1) in placeof 2-chlorobenzo[d]thiazole and heating at 135° C. overnight instead ofat 100° C. for 1 hour. MS (ISP): 299.1 ([M+H]⁺).

EXAMPLE 202-(Thiazolo[4,5-c]pyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as a white solid in analogy to example12 using 2-chlorothiazolo[4,5-c]pyridine (CAS 884860-63-3) in place of2-chlorobenzo[d]thiazole. MS (ISP): 303.2 ([M+H]⁺).

EXAMPLE 21 Methyl2-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)benzo[d]thiazole-6-carboxylate

The title compound was obtained as a yellow solid in analogy to Example12 using methyl 2-chlorobenzo[d]thiazole-6-carboxylate (CAS 90792-69-1)in place of 2-chlorobenzo[d]thiazole and heating at 125° C. overnightinstead at 100° C. for 1 hour. MS (ISP): 360.1 ([M+H]⁺).

EXAMPLE 22 Methyl 2-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)thiazole-4-carboxylate

The title compound was obtained as a white solid in analogy to Example12 using methyl 2-chlorothiazole-4-carboxylate (CAS 850429-61-7) inplace of 2-chlorobenzo[d]thiazole. MS (ISP): 310.1 ([M+H]⁺).

EXAMPLE 23 Methyl2-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)thiazole-5-carboxylate

The title compound was obtained as a white solid in analogy to Example12 using methyl 2-chlorothiazole-5-carboxylate (CAS 72605-86-8) in placeof 2-chlorobenzo[d]thiazole. MS (ISP): 310.1 ([M+H]⁺).

EXAMPLE 24 tert-Butyl6-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)nicotinate

The title compound was obtained as a white solid in analogy to Example13 using tert-butyl 6-chloronicotinate (CAS 115309-57-4) in place ofmethyl 2-chloro-1H-benzo[d]imidazole-7-carboxylate. MS (ISP): 346.2([M+H]⁺).

EXAMPLE 252-(Benzo[d]thiazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

To a mixture of 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (30mg, 147 μmol, eq. 1) and benzo[d]thiazole-6-carboxylic acid (CAS3622-35-3, 28.9 mg, 161 μmol, eq. 1.1) were added a solution of HATU inN,N-dimethylformamide 0.358 M (491 176 μmol, eq. 1.2) andN,N-diisopropylethylamine (75.8 mg, 100 586 eq. 4). The reaction mixturewas shaken at 25° C. for 4 hours. The reaction mixture was partitionedbetween water and a 1:1 mixture of ethyl acetate and tetrahydrofuran.The organic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 4 g, eluent: 0 to 10% of methanol indichloromethane) to afford2-(benzo[d]thiazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione (17mg, 51.6 μmol, 35.2%) as a white solid. MS (ISP): 330.1 ([M+H]⁺)

EXAMPLE 26 2-(4-Nitropicolinoyl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as a white solid in analogy to Example25 using 4-nitropicolinic acid (CAS 13509-19-8) in place ofbenzo[d]thiazole-6-carboxylic acid. MS (ISP): 319.1 ([M+H]⁺).

EXAMPLE 272-(2-Oxoindoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as a light brown viscous oil in analogyto Example 25 using 2-oxoindoline-4-carboxylic acid (CAS 90322-37-5) inplace of benzo[d]thiazole-6-carboxylic acid. MS (ISP): 328.2 ([M+H]⁺).

EXAMPLE 28 Methyl4-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzoate

To a mixture of 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (30mg, 147 μmol, eq. 1.2) and ethyl acetate (187 μl) were added4-(methoxycarbonyl)benzoic acid (CAS 1679-64-7, 22 mg, 122 μmol, eq. 1),pyridine (93.4 μl) and a solution of 50% 1-propanephosphonic anhydridein ethyl acetate (155 mg, 145 μl, 244 μmol, eq. 2). The reaction mixturewas shaken at 60° C. for 17 hours. The reaction mixture was partitionedbetween water and a 1:1 mixture of ethyl acetate and tetrahydrofuran.The organic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 4g, eluent: 0 to 10% of methanol indichloromethane) to afford methyl4-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzoate (27 mg, 81.7μmol, 66.9%) as a white solid. MS (ISP): 331.2 ([M+H]⁺).

EXAMPLE 292-(Benzo[d]thiazole-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

To a solution of 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (50mg, 244 μmol, eq. 1) and benzo[d]thiazole-5-carboxylic acid (CAS68867-17-4, 48.2 mg, 269 μmol, eq. 1.1) in N,N-dimethylformamide (1.5ml) were added HATU (204 mg, 537 μmol, Eq. 2.2) and DIPEA (94.7 mg, 128μl, 733 μmol, eq. 3.0) at room temperature. The reaction mixture wasstirred for 2 hours and was then partitioned between ethyl acetate (30ml) and water (15 ml). The layers were separated. The aqueous layer wasextracted with ethyl acetate (30 ml). The combined organic layers werewashed with brine (25 ml), dried over anhydrous sodium sulfate andconcentrated in vacuo. The crude material was purified by flash columnchromatography (silica gel, eluent: 0 to 5% of methanol indichloromethane) to afford2-(benzo[d]thiazole-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione (14mg, 34 μmol, 13.9%) as a white solid. MS (ISP): 330.0 ([M+H]⁺).

EXAMPLE 30 2-(5-Nitropyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as a yellow solid in analogy to Example12 using 2-chloro-5-nitropyridine (CAS 4548-45-2) in place of2-chlorobenzo[d]thiazole and heating at 100° C. for five hours insteadof one. MS (ISP): 291.1 ([M+H]⁺).

EXAMPLE 312-(2-(Pyridin-3-yl)propanoyl)-2,7-diazaspiro[4.5]decane-6,8-dione

To a mixture of 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (50mg, 244 μmol, eq. 1) and 2-(pyridin-3-yl)propanoic acid (CAS 90005-62-2,44.3 mg, 293 μmol, eq. 1.2) in ethyl acetate (560 μl) were added asolution of 1-propanephosphonic anhydride 50% in ethyl acetate (311 mg,291 489 μmol, eq. 2) and triethylamine (98.9 mg, 136 977 μmol, eq. 4).The reaction mixture was shaken at 60° C. for 3 hours. According toLC/MS, the reaction was complete. The reaction mixture was filtered andthe filtrate was directly purified by flash column chromatography(silica gel, 10g, eluent: 0 to 20% of methanol in dichloromethane) toafford 2-(2-(pyridin-3-yl)propanoyl)-2,7-diazaspiro[4.5]decane-6,8-dione(57.2 mg, 190 μmol, 77.7%) as a white solid. MS (ISP): 302.15 ([M+H]⁺).

EXAMPLE 32 Methyl 6-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)picolinate

The title compound was obtained as a brown solid in analogy to Example 6using methyl 6-chloro-2-picolinic acid methyl ester (CAS 6636-55-1) inplace of methyl 6-chloronicotinate. MS (ISP): 304.3 ([M+H]⁺).

EXAMPLE 332-(5-Nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione(Enantiomer 1)

The enantiomers of2-(5-nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione(example 9) were separated using chiral SFC (column:IC, 12 nm, 5 μm,250×4.6 mm, 20% ethanol) affording2-(5-nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione(Enantiomer 1) (24 mg, white solid), retention time=4.07 min. MS (ISP):330.3 ([M+H]⁺).

EXAMPLE 342-(5-Nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione(Enantiomer 2)

The enantiomers of 245-nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6, 8-dione (example 9) were separated using chiral SFC(column:IC, 12 nm, 5 μm, 250×4.6 mm, 20% ethanol) affording2-(5-nitro-1H-benzo[d]imidazol-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione(Enantiomer 2) (24 mg, white solid), retention time=4.55 min. MS (ISP):330.3 ([M+H]⁺).

EXAMPLE 35 2-(1-Acetylindoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

a) tert-Butyl4-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)indoline-1-carboxylate

The title compound was obtained as a light yellow solid in analogy toExample 29 using 1-(tert-butoxycarbonyl)indoline-4-carboxylic acid (CAS208774-11-2) in place of benzo[d]thiazole-5-carboxylic acid. MS (ISP):330.0 0 ([M+H]⁺).

b) 2-(Indoline-4-carbonyl)-2,7-diazaspiro [4.5]decane-6,8-dione

To a solution of tent-butyl4-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)indoline-1-carboxylate(194 mg, 469 μmol, eq. 1) in 1,4-dioxane (2 ml) was added 4 M hydrogenchloride solution in 1,4-dioxane (1.17 ml, 4.69 mmol, eq. 10) at roomtemperature. The reaction mixture was stirred for 3 days. The reactionmixture was then partitioned between ethyl acetate/tetrahydrofuran (1:1)(50 ml) and 2 M aqueous sodium carbonate (30 ml). The layers wereseparated. The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo.The crude material was purified by flashchromatography (silica gel, eluent: 0 to 10% of methanol indichloromethane) to afford2-(indoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione (102 mg, 326μmol, 69.4%) as a yellow solid. MS (ISP): 314.0 ([M+H]⁺).

c) 2-(1-Acetylindoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

To a solution of2-(indoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione (30 mg, 95.7μmol, Eq. 1) and triethylamine (19.4 mg, 26.7 191 μmol, Eq. 2.0) indichloromethane (0.5 ml) was added acetic anhydride (10.8 mg, 9.94 105μmol, Eq. 1.1) at room temperature. The reaction mixture was stirred for15 hours. The crude material was directly purified by flashchromatography (loaded as an impregnate, silica gel, eluent: 0 to 10% ofmethanol in dichloromethane) to afford2-(1-acetylindoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione (34mg, 95.7 μmol, 99.9% yield) as a white solid. MS (ISP): 356.0 ([M+H]⁺).

EXAMPLE 36 2-Benzoyl-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as a orange solid in analogy to Example29 using benzoic acid (CAS 65-85-0) in place ofbenzo[d]thiazole-5-carboxylic acid. MS (ISP): 273.0 ([M+H]⁺).

EXAMPLE 37N-(3-(6,8-Dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)acetamide

The title compound was obtained as a white solid in analogy to Example29 using 3-acetamidobenzoic acid (CAS 587-48-4) in place ofbenzo[d]thiazole-5-carboxylic acid. MS (ISP): 330.0 ([M+H]⁺).

EXAMPLE 382-(1H-Indazole-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as a white solid in analogy to Example29 using 1H-indazole-4-carboxylic acid (CAS 677306-38-6) in place ofbenzo[d]thiazole-5-carboxylic acid. MS (ISP): 313.1 ([M+H]⁺).

EXAMPLE 39 2-(5-Aminopyridin-2-yl-2,7-diazaspiro[4.5]decane-6,8-dione

To a solution of2-(5-nitropyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (189 mg, 651μmol, eq. 1) in methanol (30 ml) and tetrahydrofuran (30 ml) was added10% palladium on charcoal (34.6 mg, 32.6 μmol, eq. 0.05). The reactionmixture was stirred at room temperature for 2 hours under an atmosphereof hydrogen. The catalyst was collected by filtration, washing withmethanol. The filtrate was then concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, eluent: 0 to10% of methanol in dichloromethane) to afford2-(5-aminopyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (101 mg, 388μmol, 59.6%) as an off-white solid. MS (ISP): 287.0 ([M+H]⁺).

EXAMPLE 40 2-(Indoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was described in Example 35 (a) and (b) and wasobtained as a yellow solid. MS (ISP): 314.0 ([M+H]⁺).

EXAMPLE 41 2-(Indoline-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as a white solid in analogy to example35 a) and b) using 1-(tert-butoxycarbonyl)indoline-6-carboxylic acid(CAS 208772-41-2) in place of benzo[d]thiazole-5-carboxylic acid. MS(ISP): 314.0 ([M+H]⁺).

EXAMPLE 422-(1-Acetylindoline-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as a white solid in analogy to Example35 (c) using 2-(indoline-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione(from example 41) in place of2-(indoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione. MS (ISP):356.0 ([M+H]⁺).

EXAMPLE 43N-(6-(6,8-Dioxo-2,7-diazaspiro[4.5]decan-2-yl)pyridin-3-yl)acetamide

To a suspension of2-(5-aminopyridin-2-yl)-2,7-diazaspiro[4.5]decane-6,8-dione (17 mg, 65.3μmol, eq. 1) and Et₃N (16.5 mg, 22.8 μl, 163 μmol, eq. 2.5) indichloromethane (1 ml) was added acetic anhydride (10 mg, 9.24 μl, 98μmol, eq. 1.5). The reaction mixture was stirred at room temperature for30 minutes. The reaction mixture was poured into a mixture ofethylactate/tetrahydrofuran (1:2) and washed with water and brine. Theorganic layer was dried over sodium sulfate and concentrated in vacuo.The crude material was purified by flash chromatography (silica gel,eluent: 0 to 10% of methanol in dichloromethane) to affordN-(6-(6,8-dioxo-2,7-diazaspiro[4.5]decan-2-yl)pyridin-3-yl)acetamide (11mg, 36.4 μmol, 55.7%) as a light brown solid. MS (ISP): 303.1 ([M+H]⁺).

EXAMPLE 44 2-(Benzofuran-3-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as an off-white solid in analogy toExample 29 using benzofuran-3-carboxylic acid (CAS 26537-68-8) in placeof benzo[d]thiazole-5-carboxylic acid. MS (ISP): 313.1 ([M+H]⁺).

EXAMPLE 452-(Pyrazolo[1,5-a]pyridine-3-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as an off-white solid in analogy toExample 29 using pyrazolo[1,5-a]pyridine-3-carboxylic acid (CAS16205-46-2) in place of benzo[d]thiazole-5-carboxylic acid. MS (ISP):313.1 ([M+H]⁺).

EXAMPLE 462-(Benzo[d]oxazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as an off-white solid in analogy toExample 29 using 1,3-benzoxazole-6-carboxylic acid (CAS 154235-77-5) inplace of benzo[d]thiazole-5-carboxylic acid. MS (ISP): 314.1 ([M+H]⁺).

EXAMPLE 47 2-(Indoline-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as an off-white solid in analogy toExample 29 using indoline-5-carboxylic acid (CAS 15861-30-0) in place ofbenzo[d]thiazole-5-carboxylic acid. MS (ISP): 314.1 ([M+H]⁺).

EXAMPLE 48(+)-2-((R)-1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

To a mixture of 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride (50mg, 244 μmol, eq. 1) and (R)-1,2,3,4-tetrahydronaphthalene-1-carboxylicacid (51.7 mg, 293 μmol, eq. 1.2) in ethyl acetate (560 μl) was added asolution of 50% 1-propanephosphonic anhydride in ethyl acetate (311 mg,291 μl, 489 μmol, eq. 2) followed by triethylamine (98.9 mg, 136 977μmol, eq. 4). The reaction mixture was shaken at 60° C. for 3 hours.According to LC/MS, the reaction was finished. The reaction mixture wasfiltered and the filtrate was directly purified by flash columnchromatography (silica gel, 10 g, eluent: 0 to 20% of methanol indichloromethane). According to chiral HPLC, the compound obtained was aracemic mixture of four diastereomers. The sample was purified withchiral HPLC (column: Reprosil Chiral-NR, eluent: heptane/ethanol+NH₄OAc(70:30), pressure: 18 bar; flow rate: 35 ml/min) to afford(+)-2-((R)-1,2,3,4-tetrahydronaphthalene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione(25.6 mg, 78.4 μmol, 32.1% yield, mixture of epimers) as a white solid.Retention time=46.8 min MS (ISP): 327.3 ([M+H]⁺).

EXAMPLE 49(+2-((S)-1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

The mixture of diastereomers from Example 48 was purified with chiralHPLC (column: Reprosil Chiral-NR, eluent: heptane/ethanol+NH₄OAc(70:30), pressure: 18 bar; flow rate: 35 ml/min) to afford(−)-2-((S)-1,2,3,4-tetrahydronaphthalene-1-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione(27.9 mg, 85.5 mol, 35% yield, mixture of epimers) as a white solid .Retention time=68 min MS (ISP): 327.3 ([M+H]⁺).

EXAMPLE 50N-(5-(6,8-Dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzo[d]thiazol-2-yl)acetamide

The title compound was obtained as an off-white solid in analogy toExample 29 using 2-acetamidobenzo[d]thiazole-5-carboxylic acid (CAS77850-40-9) in place of benzo[d]thiazole-5-carboxylic acid. MS (ISP):387.1 ([M+H]⁺).

EXAMPLE 51N-(6-(6,8-Dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzo[d]thiazol-2-yl)acetamide

The title compound was obtained as an off-white solid in analogy toExample 29 using 2-acetamidobenzo[d]thiazole-6-carboxylic acid (CAS100817-94-5) in place of benzo[d]thiazole-5-carboxylic acid. MS (ISP):387.1 ([M+H]+).

EXAMPLE 522-(1-Acetylindoline-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as a white solid in analogy to Example35 (c) using 2-(indoline-5-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione(from example 47) in place of2-(indoline-4-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione. MS (ISP):356.1 ([M+H]⁺).

EXAMPLE 53 tert-Butyl(5-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzo[d]thiazol-2-yl)carbamate

The title compound was obtained as a white solid in analogy to Example29 using 2-((tert-butoxycarbonyl)amino)benzo[d]thiazole-5-carboxylicacid (CAS 1824350-51-7) in place of benzo[d]thiazole-5-carboxylic acid.MS (ISP): 445.1 ([M+H]+).

EXAMPLE 54 tert-Butyl(6-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzo[d]thiazol-2-yl)carbamate

The title compound was obtained as an off-white solid in analogy toExample 29 using2-((tert-butoxycarbonyl)amino)benzo[d]thiazole-6-carboxylic acid (CAS225525-50-8) in place of benzo[d]thiazole-5-carboxylic acid. MS (ISP):445.1 ([M+H]+).

EXAMPLE 552-(2-Aminobenzo[d]thiazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

To a stirred solution of tent-butyl(6-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)benzo[d]thiazol-2-yl)carbamate(43 mg, 96.7 μmol, eq. 1) in dichloromethane (1 ml) at room temperaturewas added dropwise trifluoroacetic acid (298 3.87 mmol, eq. 40). Thereaction mixture was stirred at room temperature for 1 h. LC-MS showedthe reaction was complete. The reaction mixture was concentrated invacuo. The residue was taken up in EtOAc/THF (1:3) and extractedsequentially with water and with brine. The organic layer was dried overNa₂SO₄ and concentrated in vacuo. The crude material was purified byflash chromatography (silica gel, 4 g, 0% to 10% MeOH in DCM) to afford2-(2-aminobenzo[d]thiazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione(14 mg, 40.7 μmol, 42% yield) as a white solid. MS (ISP): 345.0([M+H]⁺).

EXAMPLE 562-(Benzo[d]thiazole-6-carbonyl)-2,7-diazaspiro[4.5]decane-6,8-dione

The title compound was obtained as an off-white solid in analogy toExample 29 using benzo[d]thiazole-6-carboxylic acid (CAS 3622-35-3) inplace of benzo[d]thiazole-5-carboxylic acid. MS (ISP): 330.1 ([M+H]+).

EXAMPLE 578-(2-((R)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)-N-(3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)octanamide

a) tert-Butyl(8-((3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)amino)-8-oxooctyl)carbamate

2,7-Diazaspiro[4.5]decane-6,8-dione (200 mg, 1.19 mmol, eq. 1) wasdissolved in a solution of HATU in N,N-dimethylformamide (4.86 ml, 1.31mmol, eq. 1.1, 0.269 mol/l) and3-(8-((tert-butoxycarbonyl)amino)octanamido)benzoic acid (540 mg, 1.43mmol, eq. 1.2) followed by DIPEA (615 mg, 831 4.76 mmol, eq. 4) wereadded. The reaction mixture was stirred at room temperature for 3 hoursand then left overnight at room temperature. Water and ethyl acetatewere added. The aqueous phase was extracted a second time with ethylacetate. The combined organic layer was dried over sodium sulfate andconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, eluent: 0 to 50% of ethyl acetate inheptane) to afford tent-butyl(8-((3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)amino)-8-oxooctyl)carbamate(90 mg, 170 μmol, 14.3% yield) as an off-white powder. MS (ISP): 529.4([M+H]⁺).

b)8-Amino-N-(3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)octanamidehydrochloride

To a solution of tent-butyl(8-((3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)amino)-8-oxooctyl)carbamate (90 mg, 170 μmol, eq. 1) in ethyl acetate (1 ml) was added asolution of 4 M HCl in dioxane (638 μl, 2.55 mmol, eq. 15. The reactionwas stirred at room temperature for 1 hour. According to LC-MS, thereaction was finished. The solvent was evaporated. The crude wasdissolved in a minimum of ethanol and diethyl ether was added. Thesuspension obtained was filtered to afford8-amino-N-(3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)octanamidehydrochloride (40 mg, 86 μmol, 50.5% yield) and was directly used in thenext step.

c)8-(2-((R)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)-N-(3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)octanamide

(S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid (CAS 202592-23-2, 40 mg, 99.8 μmol, eq. 1) and8-amino-N-(3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)octanamidehydrochloride (51 mg, 110 μmol, eq. 1.1) were dissolved in a solution ofHATU (445 μl, 120 μmol, eq. 1.2, 0.269 mol/l) N,N-dimethylformamide andDIPEA (51.6 mg, 69.7 μl, 399 μmol, eq. 4) was added. The reactionmixture was shaken at room temperature for 3 hours. According to LC/MS,the reaction was finished. Water and dichloromethane were added. Theorganic layer was dried over sodium sulfate and concentrated in vacuo.The crude material was purified by flash chromatography (silica gel,eluent: 0 to 20% of methanol in dichloromethane) to afford8-(2-((R)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)-N-(3-(6,8-dioxo-2,7-diazaspiro[4.5]decane-2-carbonyl)phenyl)octanamide(39.8 mg, 49.1 μmol, 49.2% yield) as an off-white solid. MS (ISP): 811.3([M+H]⁺).

EXAMPLE 58(S)-8-(1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

To a solution of 1,3,8-triazaspiro[4.5]decane-2,4-dione (CAS 13625-39-3,100 mg, 591 μmol, eq. 1) and(S)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (CAS 85977-52-2, 109mg, 621 μmol, eq. 1.05) in N,N-dimethylformamide (1 ml) were added HATU(449 mg, 1.18 mmol, eq. 2.0) and DIPEA (229 mg, 310 μl, 1.77 mmol, eq.3.0) at room temperature. The reaction mixture was stirred for 15 hoursand was then partitioned between ethyl acetate (50 ml) and water (30ml). The layers were separated. The aqueous layer was extracted withethyl acetate (2×20 ml). The combined organic layers were washed withbrine (30 ml), dried over anhydrous sodium sulfate and concentrated invacuo. The crude material was purified by reversed phase HPLC followedby lyophilisation to afford(S)-8-(1,2,3,4-tetrahydronaphthalene-1-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione(45 mg, 137 μmol, 23.3%) as a white solid. MS (ISP): 328.0 ([M+H]⁺).

EXAMPLE 59(R)-8-(1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

The title compound was obtained as a white solid in analogy to Example58 using (R)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (CAS23357-47-3) in place of (9-1,2,3,4-tetrahydronaphthalene-1-carboxylicacid. MS (ISP): 328.0 ([M+H]⁺).

EXAMPLE 60 8-Benzoyl-1,3,8-triazaspiro[4.5]decane-2,4-dione

The title compound was obtained as a white solid in analogy to Example58 using benzoic acid (CAS 65-85-0) in place of(S)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid. White solid. MS(ISP): 274.1 ([M⇄H]⁺).

EXAMPLE 618-(Benzo[d]thiazol-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

To a suspension of 1,3,8-triazaspiro[4.5]decane-2,4-dione (CAS13625-39-3, 20 mg, 118 μmol, eq. 1) and DIPEA (45.8 mg, 61.9 μl, 355mol, eq. 3) in N,N-dimethylformamide (0.5 ml) was added2-chlorobenzo[d]thiazole (22.1 mg, 130 μmol, eq. 1.1). The reactionmixture was stirred at 120° C. for 2 hours. The reaction mixture waspoured into a mixture of ethylacetate/tetrahydrofuran (1:1) and theorganic layer was washed with water and brine, dried over Na₂SO₄ andconcentrated in vacuo. The crude material was purified by flash columnchromatography (silica gel, eluent: 0 to 5% of methanol indichloromethane) to afford8-(benzo[d]thiazol-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (11 mg,36.4 μmol, 30.8%) as a white solid. MS (ISP): 303.1 ([M+H]⁺).

EXAMPLE 628-(Thiazolo[4,5-b]pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

The title compound was obtained as a brown solid in analogy to Example62 using 2-chlorothiazolo[4,5-b]pyridine (CAS 152170-30-4) in place of2-chlorobenzo[d]thiazole. MS (ISP): 304.1 ([M+H]⁺).

EXAMPLE 63 Methyl6-(2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)nicotinate

The title compound was obtained as a brown solid in analogy to Example62 using methyl 6-chloronicotinate (CAS 73781-91-6) in place of2-chlorobenzo[d]thiazole and stirring for 16 hours instead of 2 hours.MS (ISP): 305.1 ([M+H]⁺).

EXAMPLE 64N-(4-(2,4-Dioxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl)phenyl)acetamide

To a solution of 1,3,8-triazaspiro[4.5]decane-2,4-dione (36 mg, 213μmol, eq. 1) and 4-acetamidobenzoic acid (CAS 556-08-1, 40 mg, 223 μmol,eq. 1.05) in N,N-dimethylformamide (1 ml) were added DIPEA (110 mg, 149μl, 851 μmol, eq. 4) and HATU (121 mg, 319 μmol, eq. 1.5). The reactionmixture was stirred at room temperature overnight. The reaction mixturewas poured into ethyl acetate/tetrahydrofuran (1:1) and extracted withwater followed with brine. The organic layer was dried over Na₂SO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 4 g, 0% to 10% methanol in dichloromethane)to affordN-(4-(2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl)phenyl)acetamide(10 mg, 30.3 14.2%) as a white solid. MS (ISP): 331.1 ([M+H]⁺).

EXAMPLE 65N-(3-(2,4-Dioxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl)phenyl)acetamide

The title compound was obtained as a white solid in analogy to Example64 using 3-acetamidobenzoic acid (CAS 587-48-4) in place of4-acetamidobenzoic acid. MS (ISP): 329.1 ([M−H]⁻).

EXAMPLE 668-(Benzofuran-3-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

To a solution of 1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride(CAS 13625-48-4, 30 mg, 146 μmol, eq. 1) and benzofuran-3-carboxylicacid (CAS 26537-68-8, 31.6 mg, 195 μmol, eq. 1.1) inN,N-dimethylformamide (0.5 ml) were added DIPEA (68.8 mg, 92.9 μL, 532μmol, eq. 3) and HATU (169 mg, 443 μmol, eq. 2.5). The reaction mixturewas stirred at room temperature for 2 hours and was poured into ethylacetate/tetrahydrofuran (2:1) (30 ml). The aqueous layer was extractedwith two portions of ethyl acetate (2×20 ml). The combined organic layerwas dried over Na₂SO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography (silica gel, 4 g, 0% to 10% methanol indichloromethane) followed by a preparative RP-HPLC and lyophilisation toafford 8-(benzofuran-3-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione(3.3 mg, 10.5 μmol, 7.22%) as a yellow solid. MS (ISP): 314.1 ([M+H]⁺).

EXAMPLE 678-(Pyrazolo[1,5-a]pyridine-3-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

The title compound was obtained as a white solid in analogy to Example66 using pyrazolo[1,5-a]pyridine-3-carboxylic acid (CAS 16205-46-2) inplace of benzofuran-3-carboxylic acid. MS (ISP): 314 ([M+H]⁺).

EXAMPLE 68 8-(Thiazolo[4,5-b]pyridin-2-yl)-2,8-diazaspiro[4.5]decane-1,3-dione

The title compound was obtained as a grey solid in analogy to Example 61using 2-chlorothiazolo[4,5-b]pyridine (CAS 152170-30-4) in place of2-chlorobenzo[d]thiazole and using 2,8-diazaspiro[4.5]decane-1,3-dionehydrochloride (CAS 2696-03-9) instead of 1,3,8-triazaspiro[4.5]decane-2,4-dione. MS (ISP): 303.1 ([M+H]⁺).

EXAMPLE 698-(5-Nitropyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

The title compound was obtained as a yellow solid in analogy to Example61 using 2-chloro-5-nitropyridine (CAS 4548-45-2) in place of2-chlorobenzo[d]thiazole. MS (ISP): 292.1 ([M+H]⁺).

EXAMPLE 70 8-(5-Nitropyridin-2-yl)-2,8-diazaspiro[4.5]decane-1,3-dione

The title compound was obtained as a grey solid in analogy to Example 61using 2-chloro-5-nitropyridine (CAS 4548-45-2) in place of2-chlorobenzo[d]thiazole and using 2,8-diazaspiro[4.5]decane-1,3-dionehydrochloride (CAS 2696-03-9) instead of1,3,8-triazaspiro[4.5]decane-2,4-dione. MS (ISP): 291.1 ([M+H]⁺).

EXAMPLE 71 8-(Benzo[d]thiazol-2-yl)-2,8-diazaspiro[4.5]decane-1,3-dione

The title compound was obtained as a grey solid in analogy to Example 61using 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride (CAS 2696-03-9)instead of 1,3,8-triazaspiro[4.5]decane-2,4-dione. MS (ISP): 302.0([M+H]⁺).

EXAMPLE 72 8-(4-Nitrophenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

The title compound was obtained as a yellow solid in analogy to Example61 using 1-fluoro-4-nitrobenzene (CAS 350-46-9) in place of2-chlorobenzo[d]thiazole. MS (ISP): 291.0 ([M+H]⁺).

EXAMPLE 73 8-(4-Nitrophenyl)-2,8-diazaspiro[4.5]decane-1,3-dione

The title compound was obtained as a grey solid in analogy to Example 61using 1-fluoro-4-nitrobenzene (CAS 350-46-9) in place of2-chlorobenzo[d]thiazole and using 2,8-diazaspiro[4.5]decane-1,3-dionehydrochloride (CAS 2696-03-9) instead of 1,3,8-triazaspiro[4.5]decane-2,4-dione. MS (ISP): 291.1 ([M+H]⁺).

EXAMPLE 74 Methyl 6-(1,3-dioxo-2,8-diazaspiro[4.5]decan-8-yl)nicotinate

The title compound was obtained as an off-white solid in analogy toExample 61 using methyl 6-chloronicotinate (CAS 73781-91-6) in place of2-chlorobenzo[d]thiazole and using 2,8-diazaspiro[4.5]decane-1,3-dionehydrochloride (CAS 2696-03-9) instead of 1,3,8-triazaspiro[4.5]decane-2,4-dione. MS (ISP): 304.1 ([M+H]⁺).

EXAMPLE 75 8-Benzoyl-2,8-diazaspiro[4.5]decane-1,3-dione

To a solution of 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride (60mg, 293 μmol, eq. 1) and triethylamine (89 mg, 123 μl, 880 μmol, eq. 3)in tetrahydrofuran (1.5 ml) was added benzoyl chloride (CAS 98-88-4,49.5 mg, 40.9 352 μmol, eq. 1.2) at 5° C. The reaction mixture wasstirred for 3 hours. LC/MS showed the reaction was finished. Thereaction mixture was partitioned between ethyl acetate/tetrahydrofuran1:1 (20 ml) and brine (25 ml). The layers were separated. The aqueouslayer was extracted with one portion of ethyl acetate (15 ml). Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 4 g, 0% to 10% methanol in dichloromethane)to afford 8-benzoyl-2,8-diazaspiro[4.5]decane-1,3-dione (25.2 mg, 92.5μmol, 31.6%) as a white solid. MS (ISP): 273.1 ([M+H]⁺).

EXAMPLE 768-(Benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione

To a suspension of benzo[d]thiazole-5-carboxylic acid (55.2 mg, 308μmol, eq. 1.05) in tetrahydrofuran (1 ml) was added1-chloro-N,N,2-trimethyl-1-propenylamine (47 mg, 46.5 μL, 352 μmol, Eq.1.2). The mixture was stirred for 1.5 hours and was added at roomtemperature in one portion to a pre-stirred suspension of2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride (60 mg, 293 μmol,eq. 1) and DIPEA (114 mg, 154 μl, 880 μmol, eq. 3.0) in tetrahydrofuran(1 ml). The reaction mixture was stirred for 1.5 hours. LC/MS showed thereaction was finished. The reaction mixture was partitioned betweenethyl acetate (30 ml) and 1 M aqueous sodium carbonate (15 ml). Theaqueous layer was extracted with one portion of ethyl acetate (30 ml).The combined organic layers were washed with one portion of brine (20ml), dried over anhydrous sodium sulfate and concentrated in vacuo. Thecrude material was purified by preparative RP-HPLC followed bylyophilisation to afford8-(benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione (16mg, 48.6 μmol, 16.6%) as a white solid. MS (ISP): 330.1 ([M+H]⁺).

EXAMPLE 77(S)-8-(1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione(or enantiomer) a) (R)-1,2,3,4-Tetrahydronaphthalene-1-carbonyl chloride

To a solution of (R)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid(250 mg, 1.42 mmol, eq. 1) in dichloromethane (11 ml) was added thionylchloride (203 mg, 124 μ1, 1.7 mmol, eq. 1.2) at room temperature and acatalytic amount of N,N-dimethylformamide. The reaction mixture wasstirred for 3 hours. The solvent was concentrated in vacuo to afford(R)-1,2,3,4-tetrahydronaphthalene-1-carbonyl chloride as a colorless oil(276 mg, 1.42 mmol, 99.9%), which was used in the next step withoutfurther purification.

b) 8-(Benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione

To a suspension of 2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride (60mg, 293 μmol, eq. 1) and triethylamine (89 mg, 123 μl, 880 μmol, eq.3.0) in tetrahydrofuran (1.5 ml) was added dropwise(R)-1,2,3,4-tetrahydronaphthalene-1-carbonyl chloride (62.8 mg, 322μmol, eq. 1.1) at 0° C.-5° C. The cooling bath was removed after 5minutes and the reaction mixture was stirred for 15 hours. The reactionwas quenched by addition of a solution of 2 M aqueous sodium carbonate(5 ml). The reaction mixture was partitioned between ethyl acetate (30ml) and a solution of 2 M aqueous sodium carbonate (15 ml). The layerswere separated. The aqueous layer was extracted with ethyl acetate (2×30ml). The combined organic layers were washed with brine (20 ml), driedover anhydrous sodium sulfate, and concentrated in vacuo. Analyticalchiral HPLC of the product revealed that some racemization had occurredduring the reaction. The crude material was purified by flash columnchromatography (silica gel, 4 g, 0% to 5% methanol in dichloromethane)to afford8-(1,2,3,4-tetrahydronaphthalene-1-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione(16 mg, 41.7 μmol, 14.2%) as a white solid. MS (ISP): 327.1 ([M+H]⁺).

c)(S)-8-(Benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione(or enantiomer)

The enantiomers of 8-(b enzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione were separated using chiral HPLC(column: Reprosil Chiral-NR, eluent: heptane/ethanol+NH₄OAc (60:40),pressure: 18 bar; flow rate: 35 ml/min) affording(S)-8-(benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione(or ENANTIOMER) (9.4 mg, white solid), retention time=8.87 min. MS(ISP): 327.1 ([M+H]⁺).

EXAMPLE 78(R)-8-(1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione(or enantiomer)

The enantiomers of8-(benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione wereseparated using chiral HPLC (column: Reprosil Chiral-NR, eluent:heptane/ethanol+NH₄OAc (60:40), pressure: 18 bar; flow rate: 35 ml/min)affording(R)-8-(benzo[d]thiazole-5-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione(or ENANTIOMER) (9.4 mg, white solid), retention time=11.28 min. MS(ISP): 327.1 ([M+H]⁺).

EXAMPLE 798-(Pyrazolo[1,5-a]pyridine-3-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione

To a suspension of pyrazolo[1,5-a]pyridine-3-carboxylic acid (CAS68867-17-4) 40 mg, 247 μmol, eq. 1) in tetrahydrofuran (0.5 ml) wasadded 1-chloro-N,N,2-trimethylpropenylamine (39.6 mg, 39.2 μl, 296 μmol,Eq. 1.2) at 0° C.-5° C. The reaction mixture was stirred at 0° C. for 30minutes to afford a white suspension. The reaction mixture was stirredat room temperature for 15 minutes and was then added to a suspension of2,8-diazaspiro[4.5]decane-1,3-dione hydrochloride (50.5 mg, 247 μmol,eq. 1) and DIPEA (95.7 mg, 129 μl, 740 μmol, eq. 3) in tetrahydrofuran(0.5 ml). The reaction mixture was stirred at room temperature for 30minutes. The reaction mixture was poured into ethylacetate/tetrahydrofuran (1:3) and extracted with brine. The organiclayer was dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, 4 g, 0% to10% MeOH in dichloromethane) to afford8-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione(42 mg, 134 μmol, 54.5%) as a white solid. MS (ISP): 313.1 ([M+H]⁺).

EXAMPLE 80 8-(Benzofuran-3-carbonyl)-2,8-diazaspiro[4.5]decane-1,3-dione

The title compound was obtained as a yellow solid in analogy to Example79 using benzofuran-3-carboxylic acid (CAS 26537-68-8) in place ofpyrazolo[1,5-a]pyridine-3-carboxylic acid. MS (ISP): 291.0 ([M+H]⁺).

EXAMPLE 818-(Benzo[d]thiazole-5-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

The title compound was obtained as a white solid in analogy to Example66 using benzo[d]thiazole-5-carboxylic acid (CAS 68867-17-4) in place ofbenzofuran-3-carboxylic acid and stirring overnight instead of for 2hours. MS (ISP): 331.1 ([M+H]⁺).

Pharmacological Tests

The compounds described herein and their pharmaceutically acceptablesalt possess valuable pharmacological properties. The compounds wereinvestigated in accordance with the test given hereinafter.

Fluorescence Direct Binding Protocol

Determination of the affinities of compounds to protein containing oneor more tryptophan is measurable by monitoring the fluorescence emissionin direct mode. The measurements, depending on the protein availableamounts, were performed either manually in a cuvette on ISS-PCI photoncounting spectrofluorometer or automatically in well plates on afluorescence plate reader device. Fluorescence titrations were performedat 20° C. in the chosen binding assay buffer by using a defined constantprotein concentration against ligand concentration variations. Smallaliquots of known ligand concentration solubilized in DMSO were addedand the fluorescence, excited at 280 nm, was recorded at 340 nm. Thefluorescence intensity was corrected for protein dilution and for thefilter effect (Birdsall, B., King, R. W., Wheeler, M. R., Lewis, C. A.Jr, Goode, S. R., Dunlap, R. B. & Roberts, G. C. (1983). Anal. Biochem.132, 353-361). The corrected fluorescence intensity was plotted againstthe ligand concentration and fitted using a four-parameter sigmoidalfunction from which the equilibrium dissociation constant K_(d) wascomputed using the law of mass action assuming a 1:1 protein—ligandcomplex (Eftink, Methods Enzymol. 1997; 278:221-57). The processincludes:

-   1) Optimization of measurement parameters to minimize protein    consumption and to minimize the dilution effect and the DMSO content-   2) Titration measurements of the protein against ligand by at least    12 titration steps to obtain an s-curve fit-   3) Repeat the same titration measurements with the ligand alone to    enable correction-   4) Check the stability of the protein once by titration against DMSO    alone-   5) Determination of the molar extinction coefficients of the ligand    at 280 and 340 nm with help of an UV- spectrophotometer-   6) Use Excel template for the correction of the measured raw data-   7) Use GraphPad Prism software for the quadratic binding fit and the    KD evaluation.

TABLE 8 Parameters of Fluorescence Direct Binding Protocol Constructname hCereblon(M1-L442)_hDDB1(M1-H1140) Concentration 2.54 mg/ml MW180180 Da Molar extinction λ₂₈₀ = 165045 M⁻¹ · cm⁻¹ coefficient Storagebuffer 20 mM MES pH 6.5 200 mM NaCl 1 mM TCEP Assay buffer 50 mM Hepes7.4 200 mM NaCl Reference Thalidomide Compound

TABLE 2 Settings for ISS-PC1 Device Excitation wavelength [nm] 280Emission wavelength [nm] 340 Cuvette Hellma 115F-QS Volume [μL] 500

TABLE 9 Protein Preparation Volume Protein Volume buffer Proteinconcentration [μL] [μL] [M] 1.8 @ 2.54 mg/ml 498.2 5.0E−8

TABLE 10 Titration Steps to determine S-Curve Fit C Aliquot V Aliquot CProt Dilution C Lig [M] [M] [μL] [M] factor     1E−10 1.0E−07 0.54.995E−08 1.001   1.1E−09 1.0E−06 0.5 4.990E−08 1.002   3.1E−09 1.0E−061 4.980E−08 1.004   5.1E−09 1.0E−06 1 4.970E−08 1.006   1.51E−08 1.0E−050.5 4.965E−08 1.007   2.51E−08 1.0E−05 0.5 4.960E−08 1.008   4.51E−081.0E−05 1 4.950E−08 1.01   6.51E−08 1.0E−05 1 4.941E−08 1.012  1.651E−071.0E−04 0.5 4.936E−08 1.013  3.651E−07 1.0E−04 1 4.926E−08 1.015 5.651E−07 1.0E−04 1 4.916E−08 1.017  7.651E−07 1.0E−04 1 4.907E−081.019  9.651E−07 1.0E−04 1 4.897E−08 1.021  1.9651E−06 1.0E−03 0.54.892E−08 1.022  2.9651E−06 1.0E−03 0.5 4.888E−08 1.023 1.29651E−051.0E−02 0.5 4.883E−08 1.024 2.29651E−05 1.0E−02 0.5 4.878E−08 1.0254.29651E−05 1.0E−02 1 4.869E−08 1.027 6.29651E−05 1.0E−02 1 4.859E−081.029 8.29651E−05 1.0E−02 1 4.850E−08 1.031

TABLE 11A Affinities of Select Compounds for Cereblon Fluorescenceh-Cereblon_DDB1 Mean Ex. Name Structure K_(d)_EQ(μM)  1 2,7-diazaspiro[4.5]decane- 6,8-dione

0.084  2 2-methyl-2,7- diazaspiro[4.5] decane-3,6,8- trione

0.159  3 2- (2-phenylacetyl)- 2,7-diazaspiro[4.5] decane-6,8-dione

0.369  4 2-(2,3-dihydro-1H- indene-1-carbonyl)- 2,7-diazaspiro[4.5]decane-6,8-dione

0.316  5 2-(3-nitrobenzoyl)- 2,7-diazaspiro[4.5] decane-6,8-dione

0.023  6 methyl 6-(6,8- dioxo-2,7- diazaspiro[4.5] decan-2-yl)nicotinate

<0.001  7 2-(thiazolo[4,5- b]pyridin-2-yl)-2,7- diazaspiro[4.5]decane-6,8-dione

<0.001  8 2-(4-nitrophenyl)- 2,7-diazaspiro[4.5] decane-6,8-dione

0.014  9 2-(5-nitro-1H- benzo[d]imidazol- 2-yl)-2,7-diazaspiro[4.5]decane- 6,8-dione

0.008 10 2-(4-nitrophenyl)- 2,7-diazaspiro[4.5] decane-6,8-dione

0.001 11 2-(4-nitrophenyl)- 2,7-diazaspiro[4.5] decane-6,8-dione

0.005 12 2-(benzo[d]thiazol- 2-yl)-2,7-diazaspiro [4.5]decane-6,8- dione

0.001 13 methyl 2-(6,8-dioxo- 2,7-diazaspiro[4.5] decan-2-yl)-1H-benzo[d]imidazole- 7-carboxylate

0.096 14 methyl 2-(6,8-dioxo- 2,7-diazaspiro[4.5] decan-2-yl)pyrimidine-4- carboxylate

0.015 15 2-(quinolin-2-yl)- 2,7-diazaspiro[4.5] decane-6,8-dione

0.006 16 2-(6- aminobenzo[d] thiazol-2-yl)-2,7- diazaspiro[4.5]decane-6,8-dione

0.010 17 2-(oxazolo[4,5-b] pyridin-2-yl)-2,7- diazaspiro[4.5]decane-6,8-dione

0.026 18 2-(benzo[d]oxazol- 2-yl)-2,7-diazaspiro [4.5]decane-6,8- dione

0.046 19 2-(1-methyl-1H- benzo[d]imidazol- 2-yl)-2,7- diazaspiro[4.5]decane-6,8-dione

0.030 20 2-(thiazolo[4,5-c] pyridin-2-yl)-2,7- diazaspiro[4.5]decane-6,8-dione

0.006 21 methyl 2-(6,8- dioxo-2,7-diazaspiro [4.5]decan-2-yl)benzo[d]thiazole- 6-carboxylate

0.008 22 methyl 2-(6,8- dioxo-2,7- diazaspiro[4.5] decan-2-yl)thiazole-4-carboxylate

0.044 23 methyl 2-(6,8- dioxo-2,7- diazaspiro[4.5] decan-2-yl)thiazole-5-carboxylate

0.008 24 tert-butyl 6-(6,8- dioxo-2,7- diazaspiro[4.5] decan-2-yl)nicotinate

0.002 25 2-(benzo[d]thiazole- 6-carbonyl)-2,7- diazaspiro[4.5]decane-6,8- dione

0.002 26 2-(4-nitropicolinoyl)- 2,7-diazaspiro[4.5] decane-6,8-dione

0.019 27 2-(2-oxoindoline- 4-carbonyl)-2,7- diazaspiro[4.5]decane-6,8-dione

0.047 28 methyl 4-(6,8-dioxo- 2,7-diazaspiro[4.5] decane-2-carbonyl)benzoate

0.013 29 2-(benzo[d]thiazole- 5-carbonyl)-2,7- diazaspiro[4.5]decane-6,8-dione

<0.001 30 2-(5-nitropyridin- 2-yl)-2,7-diazaspiro [4.5]decane-6,8- dione

0.001 31 2-(2-(pyridin-3- yl)propanoyl)-2,7- diazaspiro[4.5]decane-6,8-dione

0.077 32 methyl 6-(6,8-dioxo- 2,7diazaspiro[4.5] decan-2-yl)picolinate

0.001 33 2-(5-nitro-1H- benzo[d]imidazol- 2-yl)-2,7- diazaspiro[4.5]decane-6,8-dione

<0.001 34 2-(5-nitro-1H- benzo[d]imidazol- 2-yl)-2,7- diazaspiro[4.5]decane- 6,8-dione

0.005 35 2-(1-acetylindoline- 4- carbonyl)-2,7- diazaspiro[4.5]decane-6,8-dione

<0.001 36 2-benzoyl-2,7- diazaspiro[4.5] decane-6,8-dione

<0.001 37 N-(3-(6,8-dioxo-2,7- diazaspiro[4.5] decane-2-carbonyl)phenyl)acetamide

0.006 38 2-(1H-indazole-4- carbonyl)-2,7- diazaspiro[4.5]decane-6,8-dione

0.084 39 2-(5-aminopyridin- 2-yl)-2,7-diazaspiro [4.5]decane-6,8- dione

<0.001 40 2-(indoline-4- carbonyl)-2,7- diazaspiro[4.5] decane-6,8-dione

0.006 41 2-(indoline-6- carbonyl)-2,7- diazaspiro[4.5] decane-6,8-dione

0.075 42 2-(1- acetylindoline- 6-carbonyl)-2,7- diazaspiro[4.5]decane-6,8-dione

0.008 43 N-(6-(6,8-dioxo- 2,7-diazaspiro[4.5] decan-2-yl)pyridin-3-yl)acetamide

0.012 44 2-(benzofuran-3- carbonyl)-2,7- diazaspiro[4.5]decane-6,8-dione

0.009 45 2-(pyrazolo[1,5- a]pyridine-3- carbonyl)-2,7- diazaspiro[4.5]decane-6,8-dione

<0.001 46 2-(benzo[d] oxazole- 6-carbonyl)-2,7- diazaspiro[4.5]decane-6,8-dione

0.010 47 2-(indoline-5- carbonyl)-2,7- diazaspiro[4.5] decane-6,8-dione

0.004 48 2-((R)-1,2,3,4- tetrahydro- naphthalene-1- carbonyl)-2,7-diazaspiro[4.5] decane-6,8-dione

0.028 49 2-((S)-1,2,3,4- tetrahydro- naphthalene-1- carbonyl)-2,7-diazaspiro[4.5] decane-6,8-dione

0.014 50 N-(5-(6,8-dioxo- 2,7-diazaspiro[4.5] decane-2-carbonyl)benzo[d]thiazol-2- yl)acetamide

0.045 51 N-(6-(6,8-dioxo- 2,7-diazaspiro[4.5] decane-2-carbonyl)benzo[d]thiazol-2- yl)acetamide

0.094 52 2-(1- acetylindoline- 5-carbonyl)-2,7- diazaspiro[4.5]decane-6,8-dione

0.041 53 tert-butyl (5-(6,8- dioxo-2,7- diazaspiro[4.5]decane-2-carbonyl) benzo[d]thiazol-2- yl)carbamate

0.006 54 tert-butyl (6-(6,8- dioxo-2,7- diazaspiro[4.5]decane-2-carbonyl) benzo[d]thiazol-2- yl)carbamate

0.004 55 2-(2-aminobenzo [d]thiazole-6- carbonyl)- 2,7-diazaspiro[4.5]decane- 6,8-dione

0.026 56 2-(benzo[d] thiazole-6- carbonyl)-2,7- diazaspiro[4.5]decane-6,8-dione

0.002 57 8-(2-((R)-4-(4- chlorophenyl)- 2,3,9- trimethyl-6H-thieno[3,2-f] [1,2,4]triazolo [4,3-a] [1,4]diazepin-6- yl)acetamido)-N-(3-(6,8-dioxo-2,7- diazaspiro[4.5] decane-2- carbonyl)phenyl) octanamide

0.106

TABLE 5B Affinities of Select Compounds for Cereblon Fluorescenceh-Cereblon_DDB1 Mean Ex. Name Structure K_(d)_EQ(μM) 58 (S)-8-(1,2,3,4-tetrahydronaphthalene- 1-carbonyl)-1,3,8- triazaspiro[4.5]decane-2,4-dione

0.004 59 (R)-8-(1,2,3,4- tetrahydronaphthalene- 1-carbonyl)-1,3,8-triazaspiro[4.5]decane- 2,4-dione

0.005 60 8-benzoyl-1,3,8- triazaspiro[4.5]decane- 2,4-dione

0.002 61 8-(benzo[d]thiazol-2- yl)-1,3,8- triazaspiro[4.5]decane-2,4-dione

0.002 62 8-(thiazolo[4,5- b]pyridin-2-yl)- 1,3,8-triazaspiro[4.5]decane-2,4- dione

0.017 63 methyl 6-(2,4-dioxo- 1,3,8-triazaspiro[4.5]decan-8-yl)nicotinate

0.034 64 N-(4-(2,4-dioxo-1,3,8- triazaspiro[4.5]decane-8-carbonyl)phenyl) acetamide

0.027 65 N-(3-(2,4-dioxo- 1,3,8- triazaspiro[4.5] decane-8-carbonyl)phenyl) acetamide

0.021 66 8-(benzofuran-3- carbonyl)-1,3,8- triazaspiro[4.5]decane-2,4-dione

0.001 67 8-(pyrazolo[1,5-a] pyridine-3-carbonyl)- 1,3,8-triazaspiro[4.5]decane-2,4-dione

<0.001 68 8-(thiazolo[4,5- b]pyridin-2-yl)-2,8- diazaspiro[4.5]decane-1,3-dione

0.016 69 8-(5-nitropyridin-2- yl)-1,3,8- triazaspiro[4.5]decane-2,4-dione

0.007 70 8-(5-nitropyridin-2- yl)-2,8- diazaspiro[4.5] decane-1,3-dione

0.023 71 8-(benzo[d]thiazol-2- yl)-2,8-diazaspiro[4.5] decane-1,3-dione

0.002 72 8-(4-nitrophenyl)- 1,3,8- triazaspiro[4.5] decane-2,4-dione

<0.001 73 8-(4-nitrophenyl)- 2,8-diazaspiro[4.5] decane-1,3-dione

0.006 74 methyl 6-(1,3-dioxo- 2,8-diazaspiro[4.5] decan-8-yl)nicotinate

0.011 75 8-benzoyl-2,8- diazaspiro[4.5] decane-1,3-dione

<0.001 76 8-(benzo[d]thiazole- 5-carbonyl)-2,8- diazaspiro[4.5]decane-1,3-dione

0.015 77 (S)-8-(1,2,3,4- tetrahydronaphthalene- 1-carbonyl)-2,8-diazaspiro[4.5]decane- 1,3-dione [OR ENANTIOMER]

0.006 78 (R)-8-(1,2,3,4- tetrahydronaphthalene- 1-carbonyl)-2,8-diazaspiro[4.5]decane- 1,3-dione [OR ENANTIOMER]

0.004 79 8-(pyrazolo[1,5- a]pyridine-3- carbonyl)-2,8- diazaspiro[4.5]decane-1,3-dione

0.028 80 8-(benzofuran-3- carbonyl)-2,8- diazaspiro[4.5]decane-1,3-dione

0.006 81 8-(benzo[d]thiazole- 5-carbonyl)-1,3,8- triazaspiro[4.5]decane-2,4-dione

0.0060

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

Although the foregoing invention has been described in some detail byway of illustration and example for the purposes of clarity ofunderstanding, it will be readily apparent to one of ordinary skill inthe art in light of the teaching of this invention that certain changesand modification may be made thereto without departing from the spiritor scope of the invention as defined in the claims.

We claim:
 1. A compound selected from:

or a pharmaceutically acceptable salt thereof; wherein: A is selectedfrom the group consisting of CH₂ and NH; X^(1a) is selected from aryland aryl substituted by R^(1a); X^(1b) is selected from aryl and arylsubstituted by R^(2b); X^(1c) is selected from the group consisting ofaryl and aryl substituted with R^(2c); X^(1d) is selected from the groupconsisting of aryl and aryl substituted with R^(2d); X^(2a) is selectedfrom the group consisting of heterocyclyl, heterocyclyl substituted byR³, heteroaryl, heteroaryl substituted by R⁴, and C₁₋₆-alkyl; X^(3a) isselected from the group consisting of hydrogen, heterocyclyl,heterocyclyl substituted by R³, heteroaryl, heteroaryl substituted byR⁴, and C₁₋₆-alkyl; X^(4a) is selected from the group consisting ofhydrogen, aryl, aryl substituted by R², heterocyclyl, heterocyclylsubstituted by R³, heteroaryl, heteroaryl substituted by R⁴, andC₁₋₆-alkyl; X^(5a) is aryl substituted by R^(6a); X^(6a) is arylsubstituted with —C(═O)—OH; X^(7a) is selected from the group consistingof heteroaryl and heteroaryl substituted by R⁷; X^(8a) is heteroarylsubstituted by R^(7a); X^(B) is selected from the group consisting of:aryl; aryl substituted by R⁶; heteroaryl; and heteroaryl substituted byR⁷; Y^(B) is absent or —C(═O)—; R¹ is absent or ═O; R² is selected fromthe group consisting of: —C(═O)—O—C₁₋₆-alkyl; —NH—C(═O)—C₁₋₆-alkyl;—NH₂; —OH; and —NO₂; R^(2a) is selected from the group consisting of:—C(═O)—O—C₁₋₆-alkyl; —NH—C(═O)—C₁₋₆-alkyl; —NH₂; —OH; and —NO₂; R^(2b)is selected from the group consisting of: —C(═O)—O—C₁₋₆-alkyl;—NH—C(═O)—C₁₋₆-alkyl; —NH2; and —NO₂; R^(2c) is selected from the groupconsisting of: —C(═O)—O—C₁₋₆-alkyl; —NH—C(═O)—C₁₋₆-alkyl; and —NO₂;R^(2d) is selected from the group consisting of: —C(═O)—O—C₁₋₆-alkyl;—NH—C(═O)-C₁₋₆-alkyl; —NH₂; and —NO₂; R³ is selected from the groupconsisting of —C(═O)—C₁₋₆-alkyl and ═O; R⁴ is selected from the groupconsisting of —C(═O)—O—C₁₋₆-alkyl; C₁₋₆alkyl; —NH₂;—NH—C(═O)—C₁₋₆-alkyl; and —NO₂; R⁵ is C₁₋₆-alkyl; R⁶ is selected fromthe group consisting of: —C(═O)—OH; —NH—C(═O)—C₁₋₆-alkyl; —NH₂; and—NO₂; R^(6a) is selected from the group consisting of: —C(═O)—OH;—NH—C(═O)—C₁₋₆-alkyl; and —NO₂; R⁷ is selected from the group consistingof: —C(═O)-OH; —C(═O)—O—C₁₋₆-alkyl; —NH₂; and —NO₂; and R^(7a) isselected from the group consisting of —C(═O)—OH and —C(═O)—O—C₁₋₆-alkyl;X^(A1) is selected from the group consisting of arylene,heterocyclylene, heteroarylene, and C₁₋₆-alkylene; X^(B1) is selectedfrom the group consisting of arylene and heteroarylene; Y^(A) is absentor selected from the group consisting of: —C(═O)—;—C(═O)—C(H,C₁₋₆-alkyl)-; and —C(═O)—CH₂—; Y^(B) is absent or —C(═O)—;“Tail” is “T”; “T” is

X¹ is selected from bond, NR³⁴, CH₂, CHR³⁴, C(R³⁴)₂, O, and S; X²² isselected from halo, —NH₂, —NHR³⁴, —N(R³⁴)₂, hydroxyl, thiol, —B(OH)₂,—Sn(R³⁶)₃, —Si(R³⁶)₃, —OS(O)₂alkyl, —OS(O)₂haloalkyl, alkenyl, alkynyl,ethynyl, ethenyl, —C(O)H, —NR³⁴C(O)alkene, —NR³⁴C(O)alkyne, cyano,—SC(O)alkyl, OC(O)alkyl, heterocycle, —C(O)OH, hydrogen, alkyl, aryl,heteroaryl, aliphatic, heteroaliphatic, and carbocyclic; R³⁴ and R^(34′)are independently selected at each occurrence from hydrogen, C₁-C₆alkyl(for example methyl, ethyl, cyclopropyl, or C₁-C₃alkyl), C₁-C₆haloalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, C₃-C₆heterocycle, aryl,heteroaryl, —(CO)R³⁶, —(CS)R³⁶, —(C═NH)R³⁶, —(SO)R³⁶, and —(SO₂)R³⁶; R³⁶is independently selected at each occurrence from hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,C₃-C₆heterocycle, aryl, heteroaryl, hydroxyl, C₁-C₆alkoxy, thio,C₁-C6thioalkyl, —NH₂, —NH(C₁-C₆alkyl, C₃-C₇cycloalkyl, C₃-C₇heterocycle,aryl, or heteroaryl), and —N(independently C₁-C₆alkyl, C₃-C₇cycloalkyl,C₃-C₇heterocycle, aryl, or heteroaryl)₂; R²⁰, R²¹, R²², R²³, and R²⁴ areindependently a divalent or mutltivalent linking group, including butnot limited to a covalent bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—,—C(O)alkyl, —C(O)Oalkyl, —C(S)—, —SO₂—, —S(O)—, —C(S)—, —C(O)NH—,—NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)—, —O—, —S—, —NH—, —N(alkyl)-,—CH(—O—R²⁶)—, —CH(—NR³⁴R^(34′))—, —C(—NR³⁴R^(34′))alkyl-, —C(R⁴⁰R⁴⁰)—,-alkyl(R²⁷)-alkyl(R²⁸)—, —C(R²⁷R²⁸)—, —P(O)(OR²⁶)O—, —P(O)(OR²⁶)—,—NR³⁴C(O)NR^(34′)—, alkene, haloalkyl, alkoxy, alkyneheteroarylalkyl,aryl, arylalkyl, heterocycle, aliphatic, heteroaliphatic, heteroaryl,lactic acid, glycolic acid, carbocycle, -(ethylene₁₋₆-,-(lactic-co-glycolic acid)₁₋₆-, -(propylene glycol)₁₋₆-,—O—(CH₂)₁₋₁₂—O—, —NH—(CH₂)₁₋₁₂—NH—, —NH—(CH₂)₁₋₁₂—O—, —O—(CH₂)₁₋₁₂—NH—,—S—(CH₂)₁₋₁₂—O—, —O—(CH₂)₁₋₁₂—S—, —S—(CH₂)₁₋₁₂—S—, —S—(CH₂)₁₋₁₂—NH—, and—NH—(CH₂)₁₋₁₂—S—; each of which R²⁰, R²¹, R²², R²³, and R²⁴ isoptionally substituted with one or more substituents selected from R¹⁰¹;wherein at least one of R²⁰, R²¹, R²², R²³, and R²⁴ is not a bond; R¹⁰¹is independently selected at each occurrence from hydrogen, alkyl,alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl,heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy,heteroaryloxy, CN, —COOalkyl, COOH, NO₂, F, Cl, Br, I, CF₃, NH₂,NHalkyl, N(alkyl)₂, aliphatic, and heteroaliphatic; R²⁶ is selected fromhydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, alkyne,aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic; R²⁷ andR²⁸ are independently selected from hydrogen, alkyl, amine, or togetherwith the carbon atom to which they are attached, form C(O), C(S), C═CH₂,a C₃-C₆ spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocyclecomprising 1 or 2 heteroatoms selected from N and O, or form a 1 or 2carbon bridged ring; and R⁴⁰ is selected at each instance from:hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide,amino, cyano, —NH(aliphatic, including alkyl), -N(aliphatic, includingalkyl)₂, —NHSO₂(aliphatic, including alkyl), —N(aliphatic, includingalkyl)SO₂alkyl, —NHSO₂(aryl, heteroaryl or heterocyclic),—N(alkyl)SO₂(aryl, heteroaryl or heterocyclic) —NHSO₂alkenyl,—N(alkyl)SO₂alkenyl, —NHSO₂alkynyl, —N(alkyl)SO₂alkynyl, haloalkyl,aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, heterocyclic,and carbocyclic.
 2. The compound of claim 1, wherein the compound is ofthe formula:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, wherein R^(2a) is —NO₂.
 6. The compound of claim 1, wherein R⁴ is—NH₂, —NO₂, or —C(═O)—O—C₁₋₆-alkyl.
 7. The compound of claim 1, whereinR⁴ is C₁₋₆-alkyl or —NH—C(═O)—C₁₋₆-alkyl.
 8. The compound of claim 1,wherein R³ is —C(═O)—C₁₋₆-alkyl.
 9. The compound of claim 1, wherein R³is ═O.
 10. The compound of claim 1, wherein the compound is selectedfrom:


11. The compound of claim 1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim1, wherein R^(6a) is —NO₂.
 13. The compound of claim 1, wherein R⁶ is—NH—C(═O)—C₁₋₆-alkyl or —NO₂.
 14. The compound of claim 1, wherein R⁷ is—C(═O)—O—C₁₋₆-alkyl or —NO₂.
 15. The compound of claim 1 selected from:

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim1 selected from:

or a pharmaceutically acceptable salt thereof.
 17. The compound of claim1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 18. A method of treatingabnormal cellular proliferation in a subject in need thereof comprisingadministering an effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof
 19. The method of claim 18,wherein the subject is a human.
 20. A pharmaceutical compositioncomprising an effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof, in a pharmaceuticallyacceptable carrier.